Compositions and methods for targeting cd33-expressing cancers

ABSTRACT

Disclosed are compositions and methods for targeted treatment of CD33-expressing cancers. In particular, chimeric antigen receptor (CAR) polypeptides are disclosed that can be used with adoptive cell transfer to target and kill CD33-expressing cancers. Also disclosed are immune effector cells, such as T cells or Natural Killer (NK) cells, that are engineered to express these CARs. Therefore, also disclosed are methods of providing an anti-tumor immunity in a subject with a CD33-expressing cancer that involves adoptive transfer of the disclosed immune effector cells engineered to express the disclosed CARs. Also disclosed are multivalent antibodies are disclosed that are able to engage T-cells to destroy CD33-expressing malignant cells.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit of U.S. Provisional Application No.62/534,977, filed Jul. 20, 2017, and Application Ser. No. 62/592,107,filed Nov. 29, 2017, which are hereby incorporated herein by referencein their entirety.

BACKGROUND

Surgery, radiation therapy, and chemotherapy have been the standardaccepted approaches for treatment of cancers including leukemia, solidtumors, and metastases. Immunotherapy (sometimes called biologicaltherapy, biotherapy, or biological response modifier therapy), whichuses the body's immune system, either directly or indirectly, to shrinkor eradicate cancer has been studied for many years as an adjunct toconventional cancer therapy. It is believed that the human immune systemis an untapped resource for cancer therapy and that effective treatmentcan be developed once the components of the immune system are properlyharnessed.

SUMMARY

Compositions and methods for targeted treatment of CD33-expressingcancers are disclosed. For example, anti-CD33 antibodies are disclosedherein that are capable of selectively binding CD33-expressing cancers.Therefore, recombinant antibodies and other proteins comprising theantigen binding regions from these antibodies are also disclosed. Inparticular, anti-CD33 monoclonal antibodies from hybridomas 27A3, 33G3,36C2, 6A11, 35D5, and 38G5 are provided herein. Also disclosed arerecombinant, humanized, and/or chimeric antibodies comprising at leastthe antigen binding regions of one or more of these antibodies.

Also disclosed are multispecific, multivalent antibodies that are ableto engage T-cells to destroy CD33-expressing malignant cells. Forexample, the antibody can be a bi-specific T-cell engager. Theantibodies can be engineered from fusion polypeptides, such as fusionpolypeptides having the following formula:

V_(L)I-V_(H)I-V_(L)T-V_(H)T,

V_(L)T-V_(H)T-V_(L)I-V_(H)I,

V_(H)T-V_(L)T-V_(H)I-V_(L)I,

V_(H)I-V_(L)I-V_(H)T-V_(L)T,

V_(L)I-V_(H)I-V_(H)T-V_(L)T,

V_(L)T-V_(H)T-V_(H)I-V_(L)I,

wherein “V_(L)I” is a light chain variable domain specific for an immunecell antigen;

wherein “V_(H)T” is a heavy chain variable domain specific for CD33;

wherein “V_(L)T” is a light chain variable domain specific for CD33;

wherein “V_(H)I” is a heavy chain variable domain specific for theimmune cell antigen; and

wherein “-” consists of a peptide linker or a peptide bond.

The immune cell antigen can be a cell surface molecule that is expressedon human NK cells, T cells, monocytes, macrophages or granulocytes. Forexample, the cell surface molecule can be antigen CD2, CD3, CD16, CD64,CD89; NKp30, NKp44, NKp46, NKp80 (KLR-F1), NKG2C or NKG2D.

Also disclosed is an isolated nucleic acid encoding the disclosed fusionpolypeptide, as well as nucleic acid vectors containing this isolatednucleic acid operably linked to an expression control sequence. Alsodisclosed are cells transfected with these vectors and the use of thesecells to produce the disclosed fusion polypeptides.

Also disclosed is a pharmaceutical composition comprising a moleculedisclosed herein in a pharmaceutically acceptable carrier. Alsodisclosed is a method for treating cancer in a subject that involvesadministering to the subject a therapeutically effective amount of adisclosed pharmaceutical composition. In some cases, the cancer can beany CD33-expressing malignancy. In some cases, the cancer comprises amyelodysplastic syndrome, acute myeloid leukemia, or bi-phenotypicleukemia.

Also disclosed are chimeric antigen receptor (CAR) polypeptides that canbe used with adoptive cell transfer to target and kill CD33-expressingcancers. The disclosed CAR polypeptides contain in an ectodomain ananti-CD33 binding agent that can bind CD33-expressing cancer cells. Alsodisclosed is an immune effector cell genetically modified to express thedisclosed CAR polypeptide.

The anti-CD33 binding agent is in some embodiments an antibody fragmentthat specifically binds CD33. For example, the antigen binding domaincan be a Fab or a single-chain variable fragment (scFv) of an antibodythat specifically binds CD33. The anti-CD33 binding agent is in someembodiments an aptamer that specifically binds CD33. For example, theanti-CD33 binding agent can be a peptide aptamer selected from a randomsequence pool based on its ability to bind CD33. The anti-CD33 bindingagent can also be a natural ligand of CD33, or a variant and/or fragmentthereof capable of binding CD33.

In some embodiments, the anti-CD33 region of the disclosed antibody orCAR is derived from hybridoma 27A3, 33G3, 36C2, 6A11, 35D5, 38G5, orcombinations thereof. In some embodiments, the anti-CD33 region (e.g.scFv) can comprise a variable heavy (V_(H)) domain having CDR1, CDR2 andCDR3 sequences and a variable light (V_(L)) domain having CDR1, CDR2 andCDR3 sequences.

For example, in some embodiments, the CDR1 sequence of the V_(H) domaincomprises the amino acid sequence GFTFSNYG (SEQ ID NO:1), GYTFTSYW (SEQID NO:2), or GFSLSRYS (SEQ ID NO:3), wherein the CDR2 sequence of theV_(H) domain comprises the amino acid sequence ISSGGGDT (SEQ ID NO:4),IHPSDSET (SEQ ID NO:5), or IWGGGYT (SEQ ID NO:6), wherein the CDR3sequence of the V_(H) domain comprises the amino acid sequenceARDYGGTWDYFDY (SEQ ID NO:7), AREEGQLGHGGAMDY (SEQ ID NO:8), orARYIDSSGYDY (SEQ ID NO:9), wherein the CDR1 sequence of the V_(L)comprises the amino acid sequence QDISKY (SEQ ID NO:16), QTVNDD (SEQ IDNO:11), SSVSY (SEQ ID NO:12), or ENIYSY (SEQ ID NO:13), wherein the CDR2sequence of the V_(L) domain comprises the amino acid sequence YTSx (SEQID NO:14), YVSx (SEQ ID NO:15), DTSx (SEQ ID NO:16), or NAKx (SEQ IDNO:17), wherein the CDR3 sequence of the V_(L) domain comprises theamino acid sequence QQGDTFPVVT (SEQ ID NO:18), QQDYSSPYT (SEQ ID NO:19),QQWSSNPLT (SEQ ID NO:20), or QHHYGTPYT (SEQ ID NO:21), or anycombination thereof.

Therefore, in some embodiments, the anti-CD33 scFv V_(H) domaincomprises the amino acid sequenceEVKLVESGGGLVKPGASLKLSCAASGFTFSNYGMSWVRQTSDKRLEWVASISSGGGDTYYPDNVKGRFTISRENAKNTLYLQMSSLNSEDTALYYCARDYGGTWDYFDYW GQGTTLTVSS (SEQID NO:22), QVQLQQPGAELVRPGVSVKLSCKASGYTFTSYWMNWVKQRPGQGLEWIGMIHPSDSETRLNQKFKDKAILTVDKSSSTAYMQLSSPTSEDSAVYYCAREEGQLGHGGAM DYWGQGTSVTVSS(SEQ ID NO:23), orQVQLKESGPGLVAPSQSLSITCTVSGFSLSRYSVHWVRQPPGKGLEWLGMIWGGGYTDYNSALKSRLSISKDNSKSQVFLKMNSLQTDDTAMYYCARYIDSSGYDYWGQG TTLTVSS (SEQ IDNO:24).

In some embodiments, the anti-CD33 scFv V_(L) domain comprises the aminoacid sequence DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYYTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGDTFPWTFGGGTKLEIK (SEQ ID NO:25),SIVMTQTPKFLLVSAGDRVTITCKASQTVNDDVAWYQQKPGQSPKLLIYYVSNRHTGVPDRFTGSGYGTDFTFTISTVQAEDLAVYFCQQDYSSPYTFGGGTKLEIK (SEQ ID NO:26),QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMHWYQQKSGTSPKRWIYDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSSNPLTFGAGTKLELK (SEQ ID NO:27), orDIQMTQSPASLSASVGETVTITCRASENIYSYLAWYQQKQGKSPQLLVYNAKTLAEGVPSRFSGSGSGTQFSLKINSLQPEDFGSYYCQHHYGTPYTFGGGTKLEIK (SEQ ID NO:28).

The heavy and light chains are preferably separated by a linker.Suitable linkers for scFv antibodies are known in the art. In someembodiments, the linker comprises the amino acid sequenceGGGGSGGGGSGGGGS (SEQ ID NO:39).

In some embodiments, the anti-CD33 scFv comprises the amino acidsequence:

(SEQ ID NO: 29, 6A11HC1_LC)EVKLVESGGGLVKPGASLKLSCAASGFTFSNYGMSWVRQTSDKRLEWVASISSGGGDTYYPDNVKGRFTISRENAKNTLYLQMSSLNSEDTALYYCARDYGGTWDYFDYWGQGTTLTVSSGGGGSGGGGSGGGGSDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYYTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGDTFPWTFGGGTKLEIK.

In some embodiments, the anti-CD33 scFv comprises the amino acidsequence:

(SEQ ID NO: 30, 6A11HC2_LC)QVQLQQPGAELVRPGVSVKLSCKASGYTFTSYWMNWVKQRPGQGLEWIGMIHPSDSETRLNQKFKDKAILTVDKSSSTAYMQLSSPTSEDSAVYYCAREEGQLGHGGAMDYWGQGTSVTVSSGGGGSGGGGSGGGGSDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYYTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGDTFPWTFGGGTKLEIK.

In some embodiments, the anti-CD33 scFv comprises the amino acidsequence:

(SEQ ID NO: 31, 27A3HC_LC1)QVQLKESGPGLVAPSQSLSITCTVSGFSLSRYSVHWVRQPPGKGLEWLGMIWGGGYTDYNSALKSRLSISKDNSKSQVFLKMNSLQTDDTAMYYCARYIDSSGYDYWGQGTTLTVSSGGGGSGGGGSGGGGSSIVMTQTPKFLLVSAGDRVTITCKASQTVNDDVAWYQQKPGQSPKLLIYYVSNRHTGVPDRFTGSGYGTDFTFTISTVQAEDLAVYFCQQDYSSPYTFGGGTKLEIK.

In some embodiments, the anti-CD33 scFv comprises the amino acidsequence:

(SEQ ID NO: 32, 27A3HC_LC2)QVQLKESGPGLVAPSQSLSITCTVSGFSLSRYSVHWVRQPPGKGLEWLGMIWGGGYTDYNSALKSRLSISKDNSKSQVFLKMNSLQTDDTAMYYCARYIDSSGYDYWGQGTTLTVSSGGGGSGGGGSGGGGSQIVLTQSPAIMSASPGEKVTMTCSASSSVSYMHWYQQKSGTSPKRWIYDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSSNPLTFGAGTKLELK.

In some embodiments, the anti-CD33 scFv comprises the amino acidsequence:

(SEQ ID NO: 33, 27A3HC_LC3)QVQLKESGPGLVAPSQSLSITCTVSGFSLSRYSVHWVRQPPGKGLEWLGMIWGGGYTDYNSALKSRLSISKDNSKSQVFLKMNSLQTDDTAMYYCARYIDSSGYDYWGQGTTLTVSSGGGGSGGGGSGGGGSDIQMTQSPASLSASVGETVTITCRASENIYSYLAWYQQKQGKSPQLLVYNAKTLAEGVPSRFSGSGSGTQFSLKINSLQPEDFGSYYCQHHYGTPYTFGGGTKLEIK.

In some embodiments, the anti-CD33 scFv is encoded by the nucleic acidsequence:

(SEQ ID NO: 34, 6A11HC1_LC)ATGGCCCTCCCGGTAACGGCTCTGCTGCTTCCACTCGCACTGCTCTTGCATGCTGCCAGACCAGAAGTGAAGCTGGTGGAGTCTGGGGGAGGCTTAGTGAAGCCTGGAGCGTCTCTGAAACTCTCCTGTGCAGCCTCTGGATTCACTTTCAGTAACTATGGCATGTCTTGGGTTCGCCAGACTTCAGACAAGAGGCTGGAGTGGGTCGCATCCATTAGTAGTGGTGGTGGTGACACCTACTATCCAGACAATGTAAAGGGCCGATTCACCATCTCCAGAGAGAATGCCAAGAACACCCTGTACCTGCAAATGAGTAGTCTGAACTCTGAGGACACGGCCTTGTATTACTGTGCAAGAGACTATGGTGGTACTTGGGACTACTTTGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCAGGTGGAGGTGGATCAGGTGGAGGTGGATCTGGTGGAGGTGGATCTGATATCCAGATGACACAGACTACATCCTCCCTGTCTGCCTCTCTGGGAGACAGAGTCACCATCAGTTGCAGGGCAAGTCAGGACATTAGCAAGTATTTAAACTGGTATCAGCAGAAACCAGATGGAACTGTTAAACTCCTGATCTACTACACATCAAGATTACACTCAGGAGTCCCATCGAGGTTCAGTGGCAGTGGGTCTGGAACAGATTATTCTCTCACCATTAGCAACCTGGAGCAAGAAGATATTGCCACTTACTTTTGCCAACAGGGTGATACGTTTCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAACGG.

In some embodiments, the anti-CD33 scFv is encoded by the nucleic acidsequence:

(SEQ ID NO: 35, 6A11HC2_LC)ATGGCCCTCCCGGTAACGGCTCTGCTGCTTCCACTCGCACTGCTCTTGCATGCTGCCAGACCACAGGTCCAACTGCAGCAGCCTGGGGCTGAGCTGGTGAGGCCTGGAGTTTCAGTGAAGCTGTCCTGCAAGGCTTCTGGCTACACCTTCACCAGCTACTGGATGAACTGGGTGAAGCAGAGGCCTGGACAAGGCCTTGAGTGGATTGGCATGATTCATCCTTCCGATAGTGAAACTAGGTTAAATCAGAAGTTCAAGGACAAGGCCATATTGACTGTAGACAAATCCTCCAGCACAGCCTACATGCAACTCAGCAGCCCGACATCTGAGGACTCTGCGGTCTATTACTGTGCAAGAGAAGAGGGACAGCTCGGGCACGGCGGTGCTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCAGGTGGAGGTGGATCAGGTGGAGGTGGATCTGGTGGAGGTGGATCTGATATCCAGATGACACAGACTACATCCTCCCTGTCTGCCTCTCTGGGAGACAGAGTCACCATCAGTTGCAGGGCAAGTCAGGACATTAGCAAGTATTTAAACTGGTATCAGCAGAAACCAGATGGAACTGTTAAACTCCTGATCTACTACACATCAAGATTACACTCAGGAGTCCCATCGAGGTTCAGTGGCAGTGGGTCTGGAACAGATTATTCTCTCACCATTAGCAACCTGGAGCAAGAAGATATTGCCACTTACTTTTGCCAACAGGGTGATACGTTTCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAACGG.

In some embodiments, the anti-CD33 scFv is encoded by the nucleic acidsequence:

(SEQ ID NO: 36, 27A3HC_LC1)ATGGCCCTCCCGGTAACGGCTCTGCTGCTTCCACTCGCACTGCTCTTGCATGCTGCCAGACCACAGGTGCAGCTGAAGGAGTCAGGACCTGGCCTGGTGGCACCCTCACAGAGCCTGTCCATCACATGCACGGTCTCTGGGTTCTCATTATCCAGATATAGTGTACACTGGGTTCGCCAGCCTCCAGGAAAGGGTCTGGAGTGGCTGGGAATGATATGGGGTGGTGGATACACAGACTATAATTCAGCTCTCAAATCCAGACTGAGCATCAGCAAGGACAACTCCAAGAGCCAAGTTTTCTTAAAAATGAACAGTCTGCAAACTGATGACACAGCCATGTACTACTGTGCCAGATATATAGACAGCTCGGGCTACGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCAGGTGGAGGTGGATCAGGTGGAGGTGGATCTGGTGGAGGTGGATCTAGTATTGTGATGACCCAGACTCCCAAATTCCTGCTTGTATCAGCAGGAGACAGGGTTACCATAACCTGCAAGGCCAGTCAGACTGTGAATGATGATGTAGCTTGGTATCAACAGAAGCCAGGACAGTCTCCTAAATTGCTGATATATTATGTATCCAATCGCCACACTGGAGTCCCTGATCGCTTCACTGGCAGTGGATATGGGACGGATTTCACTTTCACCATCAGCACTGTGCAGGCTGAAGACCTGGCAGTTTATTTCTGTCAGCAGGATTATAGCTCTCCGTACACGTTCGGAGGGGGGACC AAGCTGGAAATAAAACGG.

In some embodiments, the anti-CD33 scFv is encoded by the nucleic acidsequence:

(SEQ ID NO: 37, 27A3HC_LC2)ATGGCCCTCCCGGTAACGGCTCTGCTGCTTCCACTCGCACTGCTCTTGCATGCTGCCAGACCACAGGTGCAGCTGAAGGAGTCAGGACCTGGCCTGGTGGCACCCTCACAGAGCCTGTCCATCACATGCACGGTCTCTGGGTTCTCATTATCCAGATATAGTGTACACTGGGTTCGCCAGCCTCCAGGAAAGGGTCTGGAGTGGCTGGGAATGATATGGGGTGGTGGATACACAGACTATAATTCAGCTCTCAAATCCAGACTGAGCATCAGCAAGGACAACTCCAAGAGCCAAGTTTTCTTAAAAATGAACAGTCTGCAAACTGATGACACAGCCATGTACTACTGTGCCAGATATATAGACAGCTCGGGCTACGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCAGGTGGAGGTGGATCAGGTGGAGGTGGATCTGGTGGAGGTGGATCTCAAATTGTTCTCACCCAGTCTCCAGCAATCATGTCTGCATCTCCAGGGGAGAAGGTCACCATGACCTGCAGTGCCAGCTCAAGTGTAAGTTACATGCACTGGTACCAGCAGAAGTCAGGCACCTCCCCCAAAAGATGGATTTATGACACATCCAAACTGGCTTCTGGAGTCCCTGCTCGCTTCAGTGGCAGTGGGTCTGGGACCTCTTACTCTCTCACAATCAGCAGCATGGAGGCTGAAGATGCTGCCACTTATTACTGCCAGCAGTGGAGTAGTAACCCACTCACGTTCGGTGCTGGGACCAAG CTGGAGCTGAAACGG.

In some embodiments, the anti-CD33 scFv is encoded by the nucleic acidsequence:

(SEQ ID NO: 38, 27A3HC_LC3)ATGGCCCTCCCGGTAACGGCTCTGCTGCTTCCACTCGCACTGCTCTTGCATGCTGCCAGACCACAGGTGCAGCTGAAGGAGTCAGGACCTGGCCTGGTGGCACCCTCACAGAGCCTGTCCATCACATGCACGGTCTCTGGGTTCTCATTATCCAGATATAGTGTACACTGGGTTCGCCAGCCTCCAGGAAAGGGTCTGGAGTGGCTGGGAATGATATGGGGTGGTGGATACACAGACTATAATTCAGCTCTCAAATCCAGACTGAGCATCAGCAAGGACAACTCCAAGAGCCAAGTTTTCTTAAAAATGAACAGTCTGCAAACTGATGACACAGCCATGTACTACTGTGCCAGATATATAGACAGCTCGGGCTACGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCAGGTGGAGGTGGATCAGGTGGAGGTGGATCTGGTGGAGGTGGATCTGACATCCAGATGACTCAGTCTCCAGCCTCCCTATCTGCATCTGTGGGAGAAACTGTCACCATCACATGTCGAGCAAGTGAGAATATTTACAGTTATTTAGCATGGTATCAGCAGAAACAGGGAAAATCTCCTCAGCTCCTGGTCTATAATGCAAAAACCTTAGCAGAAGGTGTGCCATCAAGGTTCAGTGGCAGTGGATCAGGCACACAGTTTTCTCTGAAGATCAACAGTCTGCAGCCTGAAGATTTTGGGAGTTATTACTGTCAACATCATTATGGTACTCCGTACACGTTCGGAGGGGGGACC AAGCTGGAAATAAAACGG.

As with other CARs, the disclosed polypeptides can also contain atransmembrane domain and an endodomain capable of activating an immuneeffector cell. For example, the endodomain can contain a signalingdomain and one or more co-stimulatory signaling regions.

In some embodiments, the intracellular signaling domain is a CD3 zeta(CD3ζ) signaling domain. In some embodiments, the costimulatorysignaling region comprises the cytoplasmic domain of CD28, 4-1BB, or acombination thereof. In some cases, the costimulatory signaling regioncontains 1, 2, 3, or 4 cytoplasmic domains of one or more intracellularsignaling and/or costimulatory molecules. In some embodiments, theco-stimulatory signaling region contains one or more mutations in thecytoplasmic domains of CD28 and/or 4-1BB that enhance signaling.

In some embodiments, the CAR polypeptide contains an incompleteendodomain. For example, the CAR polypeptide can contain only anintracellular signaling domain or a co-stimulatory domain, but not both.In these embodiments, the immune effector cell is not activated unlessit and a second CAR polypeptide (or endogenous T-cell receptor) thatcontains the missing domain both bind their respective antigens.Therefore, in some embodiments, the CAR polypeptide contains a CD3 zeta(CD3ζ) signaling domain but does not contain a costimulatory signalingregion (CSR). In other embodiments, the CAR polypeptide contains thecytoplasmic domain of CD28, 4-1BB, or a combination thereof, but doesnot contain a CD3 zeta (CD3ζ) signaling domain (SD).

Also disclosed are isolated nucleic acid sequences encoding thedisclosed CAR polypeptides, vectors comprising these isolated nucleicacids, and cells containing these vectors. For example, the cell can bean immune effector cell selected from the group consisting of analpha-beta T cells, a gamma-delta T cell, a Natural Killer (NK) cells, aNatural Killer T (NKT) cell, a B cell, an innate lymphoid cell (ILC), acytokine induced killer (CIK) cell, a cytotoxic T lymphocyte (CTL), alymphokine activated killer (LAK) cell, and a regulatory T cell. In someembodiments, the cell exhibits an anti-tumor immunity when the antigenbinding domain of the CAR binds to CD33.

In some embodiments, the cell further comprises a second CAR polypeptidecomprising a second antigen binding domain, wherein the cell exhibits ananti-tumor immunity when both the antigen binding domain of the firstCAR binds to CD33 and the antigen binding domain of the second CAR bindsto its antigen. In these embodiments, each of the first and second CARpolypeptides can have incomplete endodomains. In some embodiments, thesecond CAR polypeptide binds to CD123, TIM3, CLEC12A, CD99, NKG2Dligands, or any combination thereof.

In some embodiments, the cell further comprises a molecular suicideswitch system to remove the transferred cell population. For example,the nucleic acid encoding the CAR polypeptide can be part of anexpression cassette that also includes an accessory gene. For example,in some embodiments, the accessory gene is a truncated EGFR gene(EGFRt). An EGFRt may be used as a non-immunogenic selection tool (e.g.,immunomagnetic selection using biotinylated cetuximab in combinationwith anti-biotin microbeads for enrichment of T cells that have beenlentivirally transduced with EGFRt-containing constructs), trackingmarker (e.g., flow cytometric analysis for tracking T cell engraftment),or a suicide gene (e.g., via Cetuximab/Erbitux® mediated antibodydependent cellular cytotoxicity (ADCC) pathways). An example of atruncated EGFR (EGFRt) gene that may be used in accordance with theembodiments described herein is described in International ApplicationNo. PCT/US2010/055329, the subject matter of which is herebyincorporated by reference as if fully set forth herein. In otherembodiments, the accessory gene is a truncated CD19 gene (CD19t). Insome embodiments, the accessory gene is an inducible caspase-9 gene.

Also disclosed is a method of providing an anti-tumor immunity in asubject with a CD33-expressing cancer that involves administering to thesubject an effective amount of an immune effector cell geneticallymodified with a disclosed CD33-specific CAR.

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features,objects, and advantages of the invention will be apparent from thedescription and drawings, and from the claims.

DESCRIPTION OF DRAWINGS

FIG. 1 shows results of primary screen for anti-CD33 antibodies that wasaccomplished by incubating EL4-CD33+ and EL4-CD123+ cells with hybridomaantibodies followed by rat anti-mouse IgG fluorescent antibodies. Thiswas then detected by flow cytometry.

FIG. 2 illustrates secondary screening method for functional antibodies.

FIG. 3 shows Jurkat T cell activation measured by GFP flow cytometry forcultured EL4-CD123 or EL4-CD33 targets, hybridoma antibodies, and Jurkatcells modified to include either a CD16 or CD32 Fc receptor conjugatedto human 41BB and CD3zeta.

FIGS. 4A to 4E are CD33 CAR diagrams for 6A11HC1_LC (FIG. 4A),6A11HC2_LC (FIG. 4B), 27A3HC_LC1 (FIG. 4C), 27A3HC_LC2 (FIG. 4D), and27A3HC_LC3 (FIG. 4E).

FIG. 5 is a bar graph showing CD33 gene transfer into T cells. Genetransfer was assessed as % CD3+ and mcherry+ on live T cells. Afterde-beading T cells were stained with CD3, CD8 and CD4 (monoclonalantibodies and analyzed by using a flow cytometer.

FIG. 6 is a graph showing results of a CD33 CART cell cytotoxicityassay. Activated CD33 CAR T cells or mock transduced T cells wereco-cultured with target CHO CD33 cells, and cytotoxicity was measured ona real time cell analysis system. The data are presented as the averagenormalized cell index over time for duplicate wells. CD33 CHO cells wereleft to adhere for 16 hours to xCELLigence E-plates. CD33 CAR T cells oractivated mock transduced T cells were added to the wells of E-plateswith target cells at an E:T ratio of 10:1 for 6 days. Normalized cellindex is calculated as cell index at a given time point divided by cellindex at the normalized time point which is day 1 after addition of Tcells.

FIG. 7 is a graph showing CD33 CART cell proliferation. Activated CD33CAR T cells or un-transduced T cells were co-cultured with target CHOCD33 cells. CART cells were counted on indicated days.

FIGS. 8A to 8C are bar graph showing CD33 CART cell cytokine production.CD33 CAR T cells or mock transduced T cells were co-cultured with targetCHO CD33 cells for 24 hours. Supernatants were collected and thecytokines IFN-γ (FIG. 8A), TNF-α (FIG. 8B), and IL-6 (FIG. 8C) wereanalyzed via Luminex.

DETAILED DESCRIPTION

Disclosed herein are recombinant antibodies, such as bispecificantibodies and chimeric antigen receptors (CAR), that can specificallyrecognize tumor-associated antigens (TAA) on CD33-expressing cancers.Also disclosed are immune effector cells, such as T cells or NaturalKiller (NK) cells, that are engineered to express these CARs. Therefore,also disclosed are methods for providing an anti-tumor immunity in asubject with CD33-expressing cancers using the disclosed antibodies andimmune effector cells.

Antibodies

Antibodies that can be used in the disclosed compositions and methodsinclude whole immunoglobulin (i.e., an intact antibody) of any class,fragments thereof, and synthetic proteins containing at least theantigen binding variable domain of an antibody. The variable domainsdiffer in sequence among antibodies and are used in the binding andspecificity of each particular antibody for its particular antigen.However, the variability is not usually evenly distributed through thevariable domains of antibodies. It is typically concentrated in threesegments called complementarity determining regions (CDRs) orhypervariable regions both in the light chain and the heavy chainvariable domains. The more highly conserved portions of the variabledomains are called the framework (FR). The variable domains of nativeheavy and light chains each comprise four FR regions, largely adopting abeta-sheet configuration, connected by three CDRs, which form loopsconnecting, and in some cases forming part of, the beta-sheet structure.The CDRs in each chain are held together in close proximity by the FRregions and, with the CDRs from the other chain, contribute to theformation of the antigen binding site of antibodies.

Transgenic animals (e.g., mice) that are capable, upon immunization, ofproducing a full repertoire of human antibodies in the absence ofendogenous immunoglobulin production can be employed. For example, ithas been described that the homozygous deletion of the antibody heavychain joining region (J(H)) gene in chimeric and germ-line mutant miceresults in complete inhibition of endogenous antibody production.Transfer of the human germ-line immunoglobulin gene array in suchgerm-line mutant mice will result in the production of human antibodiesupon antigen challenge (see, e.g., Jakobovits et al., Proc. Natl. Acad.Sci. USA, 90:2551-255 (1993); Jakobovits et al., Nature, 362:255-258(1993); Bruggemann et al., Year in Immuno., 7:33 (1993)). Humanantibodies can also be produced in phage display libraries (Hoogenboomet al., J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol.,222:581 (1991)). The techniques of Cote et al. and Boerner et al. arealso available for the preparation of human monoclonal antibodies (Coleet al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77(1985); Boerner et al., J. Immunol., 147(1):86-95 (1991)).

Optionally, the antibodies are generated in other species and“humanized” for administration in humans. Humanized forms of non-human(e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulinchains or fragments thereof (such as Fv, Fab, Fab′, F(ab′)2, or otherantigen-binding subsequences of antibodies) which contain minimalsequence derived from non-human immunoglobulin. Humanized antibodiesinclude human immunoglobulins (recipient antibody) in which residuesfrom a complementarity determining region (CDR) of the recipientantibody are replaced by residues from a CDR of a non-human species(donor antibody) such as mouse, rat or rabbit having the desiredspecificity, affinity and capacity. In some instances, Fv frameworkresidues of the human immunoglobulin are replaced by correspondingnon-human residues. Humanized antibodies may also comprise residues thatare found neither in the recipient antibody nor in the imported CDR orframework sequences. In general, the humanized antibody will comprisesubstantially all of at least one, and typically two, variable domains,in which all or substantially all of the CDR regions correspond to thoseof a non-human immunoglobulin and all or substantially all of the FRregions are those of a human immunoglobulin consensus sequence. Thehumanized antibody optimally also will comprise at least a portion of animmunoglobulin constant region (Fc), typically that of a humanimmunoglobulin (Jones et al., Nature, 321:522-525 (1986); Riechmann etal., Nature, 332:323-327 (1988); and Presta, Curr. Op. Struct. Biol.,2:593-596 (1992))

Methods for humanizing non-human antibodies are well known in the art.Generally, a humanized antibody has one or more amino acid residuesintroduced into it from a source that is non-human. These non-humanamino acid residues are often referred to as “import” residues, whichare typically taken from an “import” variable domain. Antibodyhumanization techniques generally involve the use of recombinant DNAtechnology to manipulate the DNA sequence encoding one or morepolypeptide chains of an antibody molecule. Humanization can beessentially performed following the method of Winter and co-workers(Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature,332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988)), bysubstituting rodent CDRs or CDR sequences for the correspondingsequences of a human antibody. Accordingly, a humanized form of a nonhuman antibody (or a fragment thereof) is a chimeric antibody orfragment (U.S. Pat. No. 4,816,567), wherein substantially less than anintact human variable domain has been substituted by the correspondingsequence from a non-human species. In practice, humanized antibodies aretypically human antibodies in which some CDR residues and possibly someFR residues are substituted by residues from analogous sites in rodentantibodies.

Also disclosed are fragments of antibodies which have bioactivity. Thefragments, whether attached to other sequences or not, includeinsertions, deletions, substitutions, or other selected modifications ofparticular regions or specific amino acids residues, provided theactivity of the fragment is not significantly altered or impairedcompared to the non-modified antibody or antibody fragment.

Techniques can also be adapted for the production of single-chainantibodies specific to an antigenic protein of the present disclosure.Methods for the production of single-chain antibodies are well known tothose of skill in the art. A single chain antibody can be created byfusing together the variable domains of the heavy and light chains usinga short peptide linker, thereby reconstituting an antigen binding siteon a single molecule. Single-chain antibody variable fragments (scFvs)in which the C-terminus of one variable domain is tethered to theN-terminus of the other variable domain via a 15 to 25 amino acidpeptide or linker have been developed without significantly disruptingantigen binding or specificity of the binding. The linker is chosen topermit the heavy chain and light chain to bind together in their properconformational orientation.

Divalent single-chain variable fragments (di-scFvs) can be engineered bylinking two scFvs. This can be done by producing a single peptide chainwith two V_(H) and two V_(L) regions, yielding tandem scFvs. ScFvs canalso be designed with linker peptides that are too short for the twovariable regions to fold together (about five amino acids), forcingscFvs to dimerize. This type is known as diabodies. Diabodies have beenshown to have dissociation constants up to 40-fold lower thancorresponding scFvs, meaning that they have a much higher affinity totheir target. Still shorter linkers (one or two amino acids) lead to theformation of trimers (triabodies or tribodies). Tetrabodies have alsobeen produced. They exhibit an even higher affinity to their targetsthan diabodies.

A bi-specific antibody designed to selectively bind CD3 and CD33 wouldtrigger non-specific T-cell activation & cytokine storm. A bi-specificdiabody designed to selectively bind CD3 and CD33 would have a molecularweight (55-60 kD) less than the renal clearance threshold, which wouldresult in rapid elimination. As such, diabodies must be administered bya continuous infusion. The disclosed tetravalent, bi-specific antibodycan have a molecular weight (e.g., 105-110 kD) greater than the renalfiltration threshold with markedly extended PK.

Provided are fusion polypeptides capable of forming a multivalentengineered antibody that is able to engage T-cells to destroyCD33-expressing malignant cells. The engineered antibody may comprisefor example, at least one scFv, at least one Fab fragment, at least oneFv fragment, etc. It may be bivalent, trivalent, tetravalent, etc. Themultivalent antibodies is multispecific, e.g., bispecific, trispecific,tetraspecific, etc. The multivalent antibodies may be in any form, suchas a diabody, triabody, tetrabody, etc.

Bivalent and bispecific antibodies can be constructed using onlyantibody variable domains. A fairly efficient and relatively simplemethod is to make the linker sequence between the V_(H) and V_(L)domains so short that they cannot fold over and bind one another.Reduction of the linker length to 3-12 residues prevents the monomericconfiguration of the scFv molecule and favors intermolecular V_(H)-V_(L)pairings with formation of a 60 kDa non-covalent scFv dimer “diabody”.The diabody format can also be used for generation of recombinantbis-specific antibodies, which are obtained by the noncovalentassociation of two single-chain fusion products, consisting of the V_(H)domain from one antibody connected by a short linker to the V_(L) domainof another antibody. Reducing the linker length still further belowthree residues can result in the formation of trimers (“triabody”, about90 kDa) or tetramers (“tetrabody”, about 120 kDa). For a review ofengineered antibodies, particularly single domain fragments, seeHolliger and Hudson, 2005, Nature Biotechnology, 23:1126-1136. All ofsuch engineered antibodies may be used in the fusion polypeptidesprovided herein. Tetravalent Tandab® may be prepared substantially asdescribed in WO 1999057150 A3 or US20060233787, which are incorporatedby reference for the teaching of methods of making Tandab® molecules.

The antigen recognition sites or entire variable regions of theengineered antibodies may be derived from one or more parentalantibodies directed against any antigen of interest (e.g., CD33). Theparental antibodies can include naturally occurring antibodies orantibody fragments, antibodies or antibody fragments adapted fromnaturally occurring antibodies, antibodies constructed de novo usingsequences of antibodies or antibody fragments known to be specific foran antigen of interest. Sequences that may be derived from parentalantibodies include heavy and/or light chain variable regions and/orCDRs, framework regions or other portions thereof.

Multivalent, multispecific antibodies may contain a heavy chaincomprising two or more variable regions and/or a light chain comprisingone or more variable regions wherein at least two of the variableregions recognize different epitopes on the same antigen.

Candidate engineered antibodies for inclusion in the fusionpolypeptides, or the fusion polypeptides themselves, may be screened foractivity using a variety of known assays. For example, screening assaysto determine binding specificity are well known and routinely practicedin the art. For a comprehensive discussion of such assays, see Harlow etal. (Eds.), ANTIBODIES: A LABORATORY MANUAL; Cold Spring HarborLaboratory; Cold Spring Harbor, N.Y., 1988, Chapter 6.

Pharmaceutical Composition

Also disclosed is a pharmaceutical composition comprising a disclosedmolecule in a pharmaceutically acceptable carrier. Pharmaceuticalcarriers are known to those skilled in the art. These most typicallywould be standard carriers for administration of drugs to humans,including solutions such as sterile water, saline, and bufferedsolutions at physiological pH. For example, suitable carriers and theirformulations are described in Remington: The Science and Practice ofPharmacy (21 ed.) ed. PP. Gerbino, Lippincott Williams & Wilkins,Philadelphia, Pa. 2005. Typically, an appropriate amount of apharmaceutically-acceptable salt is used in the formulation to renderthe formulation isotonic. Examples of the pharmaceutically-acceptablecarrier include, but are not limited to, saline, Ringer's solution anddextrose solution. The pH of the solution is preferably from about 5 toabout 8, and more preferably from about 7 to about 7.5. The solutionshould be RNAse free. Further carriers include sustained releasepreparations such as semipermeable matrices of solid hydrophobicpolymers containing the antibody, which matrices are in the form ofshaped articles, e.g., films, liposomes or microparticles. It will beapparent to those persons skilled in the art that certain carriers maybe more preferable depending upon, for instance, the route ofadministration and concentration of composition being administered.

Pharmaceutical compositions may include carriers, thickeners, diluents,buffers, preservatives, surface active agents and the like in additionto the molecule of choice. Pharmaceutical compositions may also includeone or more active ingredients such as antimicrobial agents,anti-inflammatory agents, anesthetics, and the like.

Preparations for parenteral administration include sterile aqueous ornon-aqueous solutions, suspensions, and emulsions. Examples ofnon-aqueous solvents are propylene glycol, polyethylene glycol,vegetable oils such as olive oil, and injectable organic esters such asethyl oleate. Aqueous carriers include water, alcoholic/aqueoussolutions, emulsions or suspensions, including saline and bufferedmedia. Parenteral vehicles include sodium chloride solution, Ringer'sdextrose, dextrose and sodium chloride, lactated Ringer's, or fixedoils. Intravenous vehicles include fluid and nutrient replenishers,electrolyte replenishers (such as those based on Ringer's dextrose), andthe like. Preservatives and other additives may also be present such as,for example, antimicrobials, anti-oxidants, chelating agents, and inertgases and the like.

Some of the compositions may potentially be administered as apharmaceutically acceptable acid- or base-addition salt, formed byreaction with inorganic acids such as hydrochloric acid, hydrobromicacid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, andphosphoric acid, and organic acids such as formic acid, acetic acid,propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid,malonic acid, succinic acid, maleic acid, and fumaric acid, or byreaction with an inorganic base such as sodium hydroxide, ammoniumhydroxide, potassium hydroxide, and organic bases such as mono-, di-,trialkyl and aryl amines and substituted ethanolamines.

Methods of Treatment

Also disclosed is a method for treating a CD33-expressing cancer in asubject by administering to the subject a therapeutically effectiveamount of the disclosed pharmaceutical composition. The method canfurther involve administering to the subject a chemotherapy such asfludarabine, cytarabine, cyclophosphamide, idarubicin, daunorubicin, ora targeted inhibitor such as imbruvica, midostaurin, idelalisib, or animmune agents such as PD1 or PDL1 inhibitors.

The disclosed compositions, including pharmaceutical composition, may beadministered in a number of ways depending on whether local or systemictreatment is desired, and on the area to be treated. For example, thedisclosed compositions can be administered intravenously,intraperitoneally, intramuscularly, subcutaneously, intracavity, ortransdermally. The compositions may be administered orally, parenterally(e.g., intravenously), by intramuscular injection, by intraperitonealinjection, transdermally, extracorporeally, ophthalmically, vaginally,rectally, intranasally, topically or the like, including topicalintranasal administration or administration by inhalant.

Parenteral administration of the composition, if used, is generallycharacterized by injection. Injectables can be prepared in conventionalforms, either as liquid solutions or suspensions, solid forms suitablefor solution of suspension in liquid prior to injection, or asemulsions. A revised approach for parenteral administration involves useof a slow release or sustained release system such that a constantdosage is maintained.

The compositions disclosed herein may be administered prophylacticallyto patients or subjects who are at risk for a CD33-expressing cancer.Thus, the method can further comprise identifying a subject at risk fora CD33-expressing cancer prior to administration of the herein disclosedcompositions.

The exact amount of the compositions required will vary from subject tosubject, depending on the species, age, weight and general condition ofthe subject, the severity of the allergic disorder being treated, theparticular nucleic acid or vector used, its mode of administration andthe like. Thus, it is not possible to specify an exact amount for everycomposition. However, an appropriate amount can be determined by one ofordinary skill in the art using only routine experimentation given theteachings herein. For example, effective dosages and schedules foradministering the compositions may be determined empirically, and makingsuch determinations is within the skill in the art. The dosage rangesfor the administration of the compositions are those large enough toproduce the desired effect in which the symptoms disorder are affected.The dosage should not be so large as to cause adverse side effects, suchas unwanted cross-reactions, anaphylactic reactions, and the like.Generally, the dosage will vary with the age, condition, sex and extentof the disease in the patient, route of administration, or whether otherdrugs are included in the regimen, and can be determined by one of skillin the art. The dosage can be adjusted by the individual physician inthe event of any counterindications. Dosage can vary, and can beadministered in one or more dose administrations daily, for one orseveral days. Guidance can be found in the literature for appropriatedosages for given classes of pharmaceutical products. A typical dailydosage of the disclosed composition used alone might range from about 1μg/kg to up to 100 mg/kg of body weight or more per day, depending onthe factors mentioned above.

In some embodiments, the molecule is administered in a dose equivalentto parenteral administration of about 0.1 ng to about 100 g per kg ofbody weight, about 10 ng to about 50 g per kg of body weight, about 100ng to about 1 g per kg of body weight, from about 1 μg to about 100 mgper kg of body weight, from about 1 μg to about 50 mg per kg of bodyweight, from about 1 mg to about 500 mg per kg of body weight; and fromabout 1 mg to about 50 mg per kg of body weight. Alternatively, theamount of molecule containing lenalidomide administered to achieve atherapeutic effective dose is about 0.1 ng, 1 ng, 10 ng, 100 ng, 1 μg,10 μg, 100 μg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 500 mg perkg of body weight or greater.

CD33-Specific Chimeric Antigen Receptors (CAR)

CARs generally incorporate an antigen recognition domain from thesingle-chain variable fragments (scFv) of a monoclonal antibody (mAb)with transmembrane signaling motifs involved in lymphocyte activation(Sadelain M, et al. Nat Rev Cancer 2003 3:35-45). Disclosed herein is aCD33-specific chimeric antigen receptor (CAR) that can be that can beexpressed in immune effector cells to enhance antitumor activity againstCD33-specific CARs.

The disclosed CAR is generally made up of three domains: an ectodomain,a transmembrane domain, and an endodomain. The ectodomain comprises theCD33-binding region and is responsible for antigen recognition. It alsooptionally contains a signal peptide (SP) so that the CAR can beglycosylated and anchored in the cell membrane of the immune effectorcell. The transmembrane domain (TD), is as its name suggests, connectsthe ectodomain to the endodomain and resides within the cell membranewhen expressed by a cell. The endodomain is the business end of the CARthat transmits an activation signal to the immune effector cell afterantigen recognition. For example, the endodomain can contain a signalingdomain (ISD) and a co-stimulatory signaling region (CSR).

A “signaling domain (SD)” generally contains immunoreceptortyrosine-based activation motifs (ITAMs) that activate a signalingcascade when the ITAM is phosphorylated. The term “co-stimulatorysignaling region (CSR)” refers to intracellular signaling domains fromcostimulatory protein receptors, such as CD28, 41BB, and ICOS, that areable to enhance T-cell activation by T-cell receptors.

Also disclosed is dual CAR T cell containing the disclosed CD33-specificCAR, and at least one other CAR with a different ligand binding target.In these embodiments, one CAR can include only the CD3 domain and theother CAR can include only the co-stimulatory domain(s). In theseembodiments, dual CAR T cell activation would require co-expression ofboth targets on the target cell.

Therefore, in some embodiments, the disclosed CD33-specific CARpolypeptide contains an incomplete endodomain. For example, the CARpolypeptide can contain only an intracellular signaling domain or aco-stimulatory domain, but not both. In these embodiments, the immuneeffector cell is not activated unless it and a second CAR polypeptide(or endogenous T-cell receptor) that contains the missing domain bothbind their respective targets. Therefore, in some embodiments, the CARpolypeptide contains a CD3 zeta (CD3ζ) signaling domain but does notcontain a costimulatory signaling region (CSR). In other embodiments,the CAR polypeptide contains the cytoplasmic domain of CD28, 4-1BB, or acombination thereof, but does not contain a CD3 zeta (CD3ζ) signalingdomain (SD).

The disclosed dual CAR T cell can contain the disclosed CD33-specificCAR and at least one other CAR with a different ligand binding target,such as CD123, TIM3, or CLEC12A. CARs generally incorporate an antigenrecognition domain from the single-chain variable fragments (scFv) of amonoclonal antibody (mAb) with transmembrane signaling motifs involvedin lymphocyte activation (Sadelain M, et al. Nat Rev Cancer 20033:35-45). These additional CARs can therefore contain an antibody thatbinds the second target, such as CD123, TIM3, or CLEC12A.

In some embodiments, the intracellular signaling domain is a CD3 zeta(CD3ζ) signaling domain. In some embodiments, the costimulatorysignaling region comprises the cytoplasmic domain of CD28, 4-1BB, or acombination thereof. In some cases, the costimulatory signaling regioncontains 1, 2, 3, or 4 cytoplasmic domains of one or more intracellularsignaling and/or costimulatory molecules. In some embodiments, theco-stimulatory signaling region contains one or more mutations in thecytoplasmic domains of CD28 and/or 4-1BB that enhance signaling.

In some embodiments, the disclosed CARs comprises a costimulatorysignaling region comprising a mutated form of the cytoplasmic domain ofCD28 with altered phosphorylation at Y206 and/or Y218. In someembodiments, the disclosed CAR comprises an attenuating mutation atY206, which will reduce the activity of the CAR. In some embodiments,the disclosed CAR comprises an attenuating mutation at Y218, which willreduce expression of the CAR. Any amino acid residue, such as alanine orphenylalanine, can be substituted for the tyrosine to achieveattenuation. In some embodiments, the tyrosine at Y206 and/or Y218 issubstituted with a phosphomimetic residue. In some embodiments, thedisclosed CAR substitution of Y206 with a phosphomimetic residue, whichwill increase the activity of the CAR. In some embodiments, thedisclosed CAR comprises substitution of Y218 with a phosphomimeticresidue, which will increase expression of the CAR. For example, thephosphomimetic residue can be phosphotyrosine. In some embodiments, aCAR may contain a combination of phosphomimetic amino acids andsubstitution(s) with non-phosphorylatable amino acids in differentresidues of the same CAR. For instance, a CAR may contain an alanine orphenylalanine substitution in Y209 and/or Y191 PLUS a phosphomimeticsubstitution in Y206 and/or Y218.

In some embodiments, the disclosed CARs comprises one or more 41BBdomains with mutations that enhance binding to specific TRAF proteins,such as TRAF1, TRAF2, TRAF3, TRAF4, TRAF5, TRAF6, or any combinationthereof. In some cases, the 41BB mutation enhances TRAF1- and/orTRAF2-dependent proliferation and survival of the T-cell, e.g. throughNF-kB. In some cases, the 41BB mutation enhances TRAF3-dependentantitumor efficacy, e.g. through IRF7/INFβ. In some cases, thecytoplasmic domain of 41BB comprises the amino acid sequenceKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL (SEQ ID NO:40), where theregions of this domain responsible for TRAF binding are underlined.Therefore, the disclosed CARs can comprise cytoplasmic domain(s) of 41BBhaving at least one mutation in these underligned sequences that enhanceTRAF-binding and/or enhance NFκB signaling.

Also as disclosed herein, TRAF proteins can in some cases enhance CAR Tcell function independent of NFκB and 41BB. For example, TRAF proteinscan in some cases enhance CD28 co-stimuation in T cells. Therefore, alsodisclosed herein are immune effector cells co-expressing CARs with oneor more TRAF proteins, such as TRAF1, TRAF2, TRAF3, TRAF4, TRAF5, TRAF6,or any combination thereof. In some cases, the CAR is any CAR thattargets a tumor antigen. For example, first-generation CARs typicallyhad the intracellular domain from the CD3 chain, while second-generationCARs added intracellular signaling domains from various costimulatoryprotein receptors (e.g., CD28, 41BB, ICOS) to the endodomain of the CARto provide additional signals to the T cell. In some cases, the CAR isthe disclosed CAR with enhanced 41 BB activation.

In some embodiments, the disclosed CAR is defined by the formula:

SP-CD33-HG-TM-CSR-SD; or

SP-CD33-HG-TM-SD-CSR;

wherein “SP” represents an optional signal peptide,

wherein “CD33” represents a CD33-binding region,

wherein “HG” represents an optional hinge domain,

wherein “TM” represents a transmembrane domain,

wherein “CSR” represents one or more co-stimulatory signaling regions,

wherein “SD” represents a signaling domain, and

wherein “-” represents a peptide bond or linker.

Additional CAR constructs are described, for example, in Fresnak A D, etal. Engineered T cells: the promise and challenges of cancerimmunotherapy. Nat Rev Cancer. 2016 Aug. 23; 16(9):566-81, which isincorporated by reference in its entirety for the teaching of these CARmodels.

For example, the CAR can be a TRUCK, Universal CAR, Self-driving CAR,Armored CAR, Self-destruct CAR, Conditional CAR, Marked CAR, TenCAR,Dual CAR, or sCAR.

TRUCKs (T cells redirected for universal cytokine killing) co-express achimeric antigen receptor (CAR) and an antitumor cytokine. Cytokineexpression may be constitutive or induced by T cell activation. Targetedby CAR specificity, localized production of pro-inflammatory cytokinesrecruits endogenous immune cells to tumor sites and may potentiate anantitumor response.

Universal, allogeneic CAR T cells are engineered to no longer expressendogenous T cell receptor (TCR) and/or major histocompatibility complex(MHC) molecules, thereby preventing graft-versus-host disease (GVHD) orrejection, respectively.

Self-driving CARs co-express a CAR and a chemokine receptor, which bindsto a tumor ligand, thereby enhancing tumor homing.

CAR T cells engineered to be resistant to immunosuppression (ArmoredCARs) may be genetically modified to no longer express various immunecheckpoint molecules (for example, cytotoxic T lymphocyte-associatedantigen 4 (CTLA4) or programmed cell death protein 1 (PD1)), with animmune checkpoint switch receptor, or may be administered with amonoclonal antibody that blocks immune checkpoint signaling.

A self-destruct CAR may be designed using RNA delivered byelectroporation to encode the CAR. Alternatively, inducible apoptosis ofthe T cell may be achieved based on ganciclovir binding to thymidinekinase in gene-modified lymphocytes or the more recently describedsystem of activation of human caspase 9 by a small-molecule dimerizer.

A conditional CAR T cell is by default unresponsive, or switched ‘off’,until the addition of a small molecule to complete the circuit, enablingfull transduction of both signal 1 and signal 2, thereby activating theCAR T cell. Alternatively, T cells may be engineered to express anadaptor-specific receptor with affinity for subsequently administeredsecondary antibodies directed at target antigen.

Marked CAR T cells express a CAR plus a tumor epitope to which anexisting monoclonal antibody agent binds. In the setting of intolerableadverse effects, administration of the monoclonal antibody clears theCAR T cells and alleviates symptoms with no additional off-tumoreffects.

A tandem CAR (TanCAR) T cell expresses a single CAR consisting of twolinked single-chain variable fragments (scFvs) that have differentaffinities fused to intracellular co-stimulatory domain(s) and a CD3domain. TanCAR T cell activation is achieved only when target cellsco-express both targets.

A dual CAR T cell expresses two separate CARs with different ligandbinding targets; one CAR includes only the CD3 domain and the other CARincludes only the co-stimulatory domain(s). Dual CAR T cell activationrequires co-expression of both targets on the tumor.

A safety CAR (sCAR) consists of an extracellular scFv fused to anintracellular inhibitory domain. sCAR T cells co-expressing a standardCAR become activated only when encountering target cells that possessthe standard CAR target but lack the sCAR target.

The antigen recognition domain of the disclosed CAR is usually an scFv.There are however many alternatives. An antigen recognition domain fromnative T-cell receptor (TCR) alpha and beta single chains have beendescribed, as have simple ectodomains (e.g. CD4 ectodomain to recognizeHIV infected cells) and more exotic recognition components such as alinked cytokine (which leads to recognition of cells bearing thecytokine receptor). In fact almost anything that binds a given targetwith high affinity can be used as an antigen recognition region.

The endodomain is the business end of the CAR that after antigenrecognition transmits a signal to the immune effector cell, activatingat least one of the normal effector functions of the immune effectorcell. Effector function of a T cell, for example, may be cytolyticactivity or helper activity including the secretion of cytokines.Therefore, the endodomain may comprise the “intracellular signalingdomain” of a T cell receptor (TCR) and optional co-receptors. Whileusually the entire intracellular signaling domain can be employed, inmany cases it is not necessary to use the entire chain. To the extentthat a truncated portion of the intracellular signaling domain is used,such truncated portion may be used in place of the intact chain as longas it transduces the effector function signal.

Cytoplasmic signaling sequences that regulate primary activation of theTCR complex that act in a stimulatory manner may contain signalingmotifs which are known as immunoreceptor tyrosine-based activationmotifs (ITAMs). Examples of ITAM containing cytoplasmic signalingsequences include those derived from CD8, CD3ζ, CD3δ, CD3γ, CD3ε, CD32(Fc gamma RIIa), DAP10, DAP12, CD79a, CD79b, FcγRIγ, FcγRIIIγ, FcεRIβ(FCERIB), and FcεRIγ (FCERIG).

In particular embodiments, the intracellular signaling domain is derivedfrom CD3 zeta (CD3ζ) (TCR zeta, GenBank accno. BAG36664.1). T-cellsurface glycoprotein CD3 zeta (CD3ζ) chain, also known as T-cellreceptor T3 zeta chain or CD247 (Cluster of Differentiation 247), is aprotein that in humans is encoded by the CD247 gene.

First-generation CARs typically had the intracellular domain from theCD3 chain, which is the primary transmitter of signals from endogenousTCRs. Second-generation CARs add intracellular signaling domains fromvarious costimulatory protein receptors (e.g., CD28, 41BB, ICOS) to theendodomain of the CAR to provide additional signals to the T cell.Preclinical studies have indicated that the second generation of CARdesigns improves the antitumor activity of T cells. More recent,third-generation CARs combine multiple signaling domains to furtheraugment potency. T cells grafted with these CARs have demonstratedimproved expansion, activation, persistence, and tumor-eradicatingefficiency independent of costimulatory receptor/ligand interaction(Imai C, et al. Leukemia 2004 18:676-84; Maher J, et al. Nat Biotechnol2002 20:70-5).

For example, the endodomain of the CAR can be designed to comprise theCD3ζ signaling domain by itself or combined with any other desiredcytoplasmic domain(s) useful in the context of the CAR of the invention.For example, the cytoplasmic domain of the CAR can comprise a CD3ζ chainportion and a costimulatory signaling region. The costimulatorysignaling region refers to a portion of the CAR comprising theintracellular domain of a costimulatory molecule. A costimulatorymolecule is a cell surface molecule other than an antigen receptor ortheir ligands that is required for an efficient response of lymphocytesto an antigen. Examples of such molecules include CD27, CD28, 4-1BB(CD137), OX40, CD30, CD40, ICOS, lymphocyte function-associatedantigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, and a ligand thatspecifically binds with CD83, CD8, CD4, b2c, CD80, CD86, DAP10, DAP12,MyD88, BTNL3, and NKG2D. Thus, while the CAR is exemplified primarilywith CD28 as the co-stimulatory signaling element, other costimulatoryelements can be used alone or in combination with other co-stimulatorysignaling elements.

In some embodiments, the CAR comprises a hinge sequence. A hingesequence is a short sequence of amino acids that facilitates antibodyflexibility (see, e.g., Woof et al., Nat. Rev. Immunol., 4(2): 89-99(2004)). The hinge sequence may be positioned between the antigenrecognition moiety (e.g., anti-CD33 scFv) and the transmembrane domain.The hinge sequence can be any suitable sequence derived or obtained fromany suitable molecule. In some embodiments, for example, the hingesequence is derived from a CD8a molecule or a CD28 molecule.

The transmembrane domain may be derived either from a natural or from asynthetic source. Where the source is natural, the domain may be derivedfrom any membrane-bound or transmembrane protein. For example, thetransmembrane region may be derived from (i.e. comprise at least thetransmembrane region(s) of) the alpha, beta or zeta chain of the T-cellreceptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8 (e.g., CD8 alpha, CD8beta), CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, orCD154, KIRDS2, OX40, CD2, CD27, LFA-1 (CD11a, CD18), ICOS (CD278), 4-1BB(CD137), GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD160,CD19, IL2R beta, IL2R gamma, IL7R α, ITGA1, VLA1, CD49a, ITGA4, IA4,CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a,LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1,ITGB7, TNFR2, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile),CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), SLAMF6(NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG(CD162), LTBR, and PAG/Cbp. Alternatively the transmembrane domain maybe synthetic, in which case it will comprise predominantly hydrophobicresidues such as leucine and valine. In some cases, a triplet ofphenylalanine, tryptophan and valine will be found at each end of asynthetic transmembrane domain. A short oligo- or polypeptide linker,such as between 2 and 10 amino acids in length, may form the linkagebetween the transmembrane domain and the endoplasmic domain of the CAR.

In some embodiments, the CAR has more than one transmembrane domain,which can be a repeat of the same transmembrane domain, or can bedifferent transmembrane domains.

In some embodiments, the CAR is a multi-chain CAR, as described inWO2015/039523, which is incorporated by reference for this teaching. Amulti-chain CAR can comprise separate extracellular ligand binding andsignaling domains in different transmembrane polypeptides. The signalingdomains can be designed to assemble in juxtamembrane position, whichforms flexible architecture closer to natural receptors, that confersoptimal signal transduction. For example, the multi-chain CAR cancomprise a part of an FCERI alpha chain and a part of an FCERI betachain such that the FCERI chains spontaneously dimerize together to forma CAR.

Tables 1, 2, and 3 below provide some example combinations ofCD33-binding region, co-stimulatory signaling regions, and intracellularsignaling domain that can occur in the disclosed CARs.

TABLE 1 First Generation CARs ScFv Signal Domain CD33 CD8 CD33 CD3ζ CD33CD3δ CD33 CD3γ CD33 CD3ε CD33 FcγRI-γ CD33 FcγRIII-γ CD33 FcεRIβ CD33FcεRIγ CD33 DAP10 CD33 DAP12 CD33 CD32 CD33 CD79a

TABLE 2 Second Generation CARs Co-stimulatory Signal Co-stimulatorySignal ScFv Signal Domain ScFv Signal Domain CD33 CD28 CD8 CD33 CD80FcεRIβ CD33 CD28 CD3ζ CD33 CD80 FcεRIγ CD33 CD28 CD3δ CD33 CD80 DAP10CD33 CD28 CD3γ CD33 CD80 DAP12 CD33 CD28 CD3ε CD33 CD80 CD32 CD33 CD28FcγRI-γ CD33 CD80 CD79a CD33 CD28 FcγRIII-γ CD33 CD80 CD79b CD33 CD28FcεRIβ CD33 CD86 CD8 CD33 CD28 FcεRIγ CD33 CD86 CD3ζ CD33 CD28 DAP10CD33 CD86 CD3δ CD33 CD28 DAP12 CD33 CD86 CD3γ CD33 CD28 CD32 CD33 CD86CD3ε CD33 CD28 CD79a CD33 CD86 FcγRI-γ CD33 CD28 CD79b CD33 CD86FcγRIII-γ CD33 CD8 CD8 CD33 CD86 FcεRIβ CD33 CD8 CD3ζ CD33 CD86 FcεRIγCD33 CD8 CD3δ CD33 CD86 DAP10 CD33 CD8 CD3γ CD33 CD86 DAP12 CD33 CD8CD3ε CD33 CD86 CD32 CD33 CD8 FcγRI-γ CD33 CD86 CD79a CD33 CD8 FcγRIII-γCD33 CD86 CD79b CD33 CD8 FcεRIβ CD33 OX40 CD8 CD33 CD8 FcεRIγ CD33 OX40CD3ζ CD33 CD8 DAP10 CD33 OX40 CD3δ CD33 CD8 DAP12 CD33 OX40 CD3γ CD33CD8 CD32 CD33 OX40 CD3ε CD33 CD8 CD79a CD33 OX40 FcγRI-γ CD33 CD8 CD79bCD33 OX40 FcγRIII-γ CD33 CD4 CD8 CD33 OX40 FcεRIβ CD33 CD4 CD3ζ CD33OX40 FcεRIγ CD33 CD4 CD3δ CD33 OX40 DAP10 CD33 CD4 CD3γ CD33 OX40 DAP12CD33 CD4 CD3ε CD33 OX40 CD32 CD33 CD4 FcγRI-γ CD33 OX40 CD79a CD33 CD4FcγRIII-γ CD33 OX40 CD79b CD33 CD4 FcεRIβ CD33 DAP10 CD8 CD33 CD4 FcεRIγCD33 DAP10 CD3ζ CD33 CD4 DAP10 CD33 DAP10 CD3δ CD33 CD4 DAP12 CD33 DAP10CD3γ CD33 CD4 CD32 CD33 DAP10 CD3ε CD33 CD4 CD79a CD33 DAP10 FcγRI-γCD33 CD4 CD79b CD33 DAP10 FcγRIII-γ CD33 b2c CD8 CD33 DAP10 FcεRIβ CD33b2c CD3ζ CD33 DAP10 FcεRIγ CD33 b2c CD3δ CD33 DAP10 DAP10 CD33 b2c CD3γCD33 DAP10 DAP12 CD33 b2c CD3ε CD33 DAP10 CD32 CD33 b2c FcγRI-γ CD33DAP10 CD79a CD33 b2c FcγRIII-γ CD33 DAP10 CD79b CD33 b2c FcεRIβ CD33DAP12 CD8 CD33 b2c FcεRIγ CD33 DAP12 CD3ζ CD33 b2c DAP10 CD33 DAP12 CD3δCD33 b2c DAP12 CD33 DAP12 CD3γ CD33 b2c CD32 CD33 DAP12 CD3ε CD33 b2cCD79a CD33 DAP12 FcγRI-γ CD33 b2c CD79b CD33 DAP12 FcγRIII-γ CD33CD137/41BB CD8 CD33 DAP12 FcεRIβ CD33 CD137/41BB CD3ζ CD33 DAP12 FcεRIγCD33 CD137/41BB CD3δ CD33 DAP12 DAP10 CD33 CD137/41BB CD3γ CD33 DAP12DAP12 CD33 CD137/41BB CD3ε CD33 DAP12 CD32 CD33 CD137/41BB FcγRI-γ CD33DAP12 CD79a CD33 CD137/41BB FcγRIII-γ CD33 DAP12 CD79b CD33 CD137/41BBFcεRIβ CD33 MyD88 CD8 CD33 CD137/41BB FcεRIγ CD33 MyD88 CD3ζ CD33CD137/41BB DAP10 CD33 MyD88 CD3δ CD33 CD137/41BB DAP12 CD33 MyD88 CD3γCD33 CD137/41BB CD32 CD33 MyD88 CD3ε CD33 CD137/41BB CD79a CD33 MyD88FcγRI-γ CD33 CD137/41BB CD79b CD33 MyD88 FcγRIII-γ CD33 ICOS CD8 CD33MyD88 FcεRIβ CD33 ICOS CD3ζ CD33 MyD88 FcεRIγ CD33 ICOS CD3δ CD33 MyD88DAP10 CD33 ICOS CD3γ CD33 MyD88 DAP12 CD33 ICOS CD3ε CD33 MyD88 CD32CD33 ICOS FcγRI-γ CD33 MyD88 CD79a CD33 ICOS FcγRIII-γ CD33 MyD88 CD79bCD33 ICOS FcεRIβ CD33 CD7 CD8 CD33 ICOS FcεRIγ CD33 CD7 CD3ζ CD33 ICOSDAP10 CD33 CD7 CD3δ CD33 ICOS DAP12 CD33 CD7 CD3γ CD33 ICOS CD32 CD33CD7 CD3ε CD33 ICOS CD79a CD33 CD7 FcγRI-γ CD33 ICOS CD79b CD33 CD7FcγRIII-γ CD33 CD27 CD8 CD33 CD7 FcεRIβ CD33 CD27 CD3ζ CD33 CD7 FcεRIγCD33 CD27 CD3δ CD33 CD7 DAP10 CD33 CD27 CD3γ CD33 CD7 DAP12 CD33 CD27CD3ε CD33 CD7 CD32 CD33 CD27 FcγRI-γ CD33 CD7 CD79a CD33 CD27 FcγRIII-γCD33 CD7 CD79b CD33 CD27 FcεRIβ CD33 BTNL3 CD8 CD33 CD27 FcεRIγ CD33BTNL3 CD3ζ CD33 CD27 DAP10 CD33 BTNL3 CD3δ CD33 CD27 DAP12 CD33 BTNL3CD3γ CD33 CD27 CD32 CD33 BTNL3 CD3ε CD33 CD27 CD79a CD33 BTNL3 FcγRI-γCD33 CD27 CD79b CD33 BTNL3 FcγRIII-γ CD33 CD28δ CD8 CD33 BTNL3 FcεRIβCD33 CD28δ CD3ζ CD33 BTNL3 FcεRIγ CD33 CD28δ CD3δ CD33 BTNL3 DAP10 CD33CD28δ CD3γ CD33 BTNL3 DAP12 CD33 CD28δ CD3ε CD33 BTNL3 CD32 CD33 CD28δFcγRI-γ CD33 BTNL3 CD79a CD33 CD28δ FcγRIII-γ CD33 BTNL3 CD79b CD33CD28δ FcεRIβ CD33 NKG2D CD8 CD33 CD28δ FcεRIγ CD33 NKG2D CD3ζ CD33 CD28δDAP10 CD33 NKG2D CD3δ CD33 CD28δ DAP12 CD33 NKG2D CD3γ CD33 CD28δ CD32CD33 NKG2D CD3ε CD33 CD28δ CD79a CD33 NKG2D FcγRI-γ CD33 CD28δ CD79bCD33 NKG2D FcγRIII-γ CD33 CD80 CD8 CD33 NKG2D FcεRIβ CD33 CD80 CD3ζ CD33NKG2D FcεRIγ CD33 CD80 CD3δ CD33 NKG2D DAP10 CD33 CD80 CD3γ CD33 NKG2DDAP12 CD33 CD80 CD3ε CD33 NKG2D CD32 CD33 CD80 FcγRI-γ CD33 NKG2D CD79aCD33 CD80 FcγRIII-γ CD33 NKG2D CD79b

TABLE 3 Third Generation CARs Co-stimulatory Co-stimulatory Signal ScFvSignal Signal Domain CD33 CD28 CD28 CD8 CD33 CD28 CD28 CD3ζ CD33 CD28CD28 CD3δ CD33 CD28 CD28 CD3γ CD33 CD28 CD28 CD3ε CD33 CD28 CD28 FcγRI-γCD33 CD28 CD28 FcγRIII-γ CD33 CD28 CD28 FcεRIβ CD33 CD28 CD28 FcεRIγCD33 CD28 CD28 DAP10 CD33 CD28 CD28 DAP12 CD33 CD28 CD28 CD32 CD33 CD28CD28 CD79a CD33 CD28 CD28 CD79b CD33 CD28 CD8 CD8 CD33 CD28 CD8 CD3ζCD33 CD28 CD8 CD3δ CD33 CD28 CD8 CD3γ CD33 CD28 CD8 CD3ε CD33 CD28 CD8FcγRI-γ CD33 CD28 CD8 FcγRIII-γ CD33 CD28 CD8 FcεRIβ CD33 CD28 CD8FcεRIγ CD33 CD28 CD8 DAP10 CD33 CD28 CD8 DAP12 CD33 CD28 CD8 CD32 CD33CD28 CD8 CD79a CD33 CD28 CD8 CD79b CD33 CD28 CD4 CD8 CD33 CD28 CD4 CD3ζCD33 CD28 CD4 CD3δ CD33 CD28 CD4 CD3γ CD33 CD28 CD4 CD3ε CD33 CD28 CD4FcγRI-γ CD33 CD28 CD4 FcγRIII-γ CD33 CD28 CD4 FcεRIβ CD33 CD28 CD4FcεRIγ CD33 CD28 CD4 DAP10 CD33 CD28 CD4 DAP12 CD33 CD28 CD4 CD32 CD33CD28 CD4 CD79a CD33 CD28 CD4 CD79b CD33 CD28 b2c CD8 CD33 CD28 b2c CD3ζCD33 CD28 b2c CD3δ CD33 CD28 b2c CD3γ CD33 CD28 b2c CD3ε CD33 CD28 b2cFcγRI-γ CD33 CD28 b2c FcγRIII-γ CD33 CD28 b2c FcεRIβ CD33 CD28 b2cFcεRIγ CD33 CD28 b2c DAP10 CD33 CD28 b2c DAP12 CD33 CD28 b2c CD32 CD33CD28 b2c CD79a CD33 CD28 b2c CD79b CD33 CD28 CD137/41BB CD8 CD33 CD28CD137/41BB CD3ζ CD33 CD28 CD137/41BB CD3δ CD33 CD28 CD137/41BB CD3γ CD33CD28 CD137/41BB CD3ε CD33 CD28 CD137/41BB FcγRI-γ CD33 CD28 CD137/41BBFcγRIII-γ CD33 CD28 CD137/41BB FcεRIβ CD33 CD28 CD137/41BB FcεRIγ CD33CD28 CD137/41BB DAP10 CD33 CD28 CD137/41BB DAP12 CD33 CD28 CD137/41BBCD32 CD33 CD28 CD137/41BB CD79a CD33 CD28 CD137/41BB CD79b CD33 CD28ICOS CD8 CD33 CD28 ICOS CD3ζ CD33 CD28 ICOS CD3δ CD33 CD28 ICOS CD3γCD33 CD28 ICOS CD3ε CD33 CD28 ICOS FcγRI-γ CD33 CD28 ICOS FcγRIII-γ CD33CD28 ICOS FcεRIβ CD33 CD28 ICOS FcεRIγ CD33 CD28 ICOS DAP10 CD33 CD28ICOS DAP12 CD33 CD28 ICOS CD32 CD33 CD28 ICOS CD79a CD33 CD28 ICOS CD79bCD33 CD28 CD27 CD8 CD33 CD28 CD27 CD3ζ CD33 CD28 CD27 CD3δ CD33 CD28CD27 CD3γ CD33 CD28 CD27 CD3ε CD33 CD28 CD27 FcγRI-γ CD33 CD28 CD27FcγRIII-γ CD33 CD28 CD27 FcεRIβ CD33 CD28 CD27 FcεRIγ CD33 CD28 CD27DAP10 CD33 CD28 CD27 DAP12 CD33 CD28 CD27 CD32 CD33 CD28 CD27 CD79a CD33CD28 CD27 CD79b CD33 CD28 CD28δ CD8 CD33 CD28 CD28δ CD3ζ CD33 CD28 CD28δCD3δ CD33 CD28 CD28δ CD3γ CD33 CD28 CD28δ CD3ε CD33 CD28 CD28δ FcγRI-γCD33 CD28 CD28δ FcγRIII-γ CD33 CD28 CD28δ FcεRIβ CD33 CD28 CD28δ FcεRIγCD33 CD28 CD28δ DAP10 CD33 CD28 CD28δ DAP12 CD33 CD28 CD28δ CD32 CD33CD28 CD28δ CD79a CD33 CD28 CD28δ CD79b CD33 CD28 CD80 CD8 CD33 CD28 CD80CD3ζ CD33 CD28 CD80 CD3δ CD33 CD28 CD80 CD3γ CD33 CD28 CD80 CD3ε CD33CD28 CD80 FcγRI-γ CD33 CD28 CD80 FcγRIII-γ CD33 CD28 CD80 FcεRIβ CD33CD28 CD80 FcεRIγ CD33 CD28 CD80 DAP10 CD33 CD28 CD80 DAP12 CD33 CD28CD80 CD32 CD33 CD28 CD80 CD79a CD33 CD28 CD80 CD79b CD33 CD28 CD86 CD8CD33 CD28 CD86 CD3ζ CD33 CD28 CD86 CD3δ CD33 CD28 CD86 CD3γ CD33 CD28CD86 CD3ε CD33 CD28 CD86 FcγRI-γ CD33 CD28 CD86 FcγRIII-γ CD33 CD28 CD86FcεRIβ CD33 CD28 CD86 FcεRIγ CD33 CD28 CD86 DAP10 CD33 CD28 CD86 DAP12CD33 CD28 CD86 CD32 CD33 CD28 CD86 CD79a CD33 CD28 CD86 CD79b CD33 CD28OX40 CD8 CD33 CD28 OX40 CD3ζ CD33 CD28 OX40 CD3δ CD33 CD28 OX40 CD3γCD33 CD28 OX40 CD3ε CD33 CD28 OX40 FcγRI-γ CD33 CD28 OX40 FcγRIII-γ CD33CD28 OX40 FcεRIβ CD33 CD28 OX40 FcεRIγ CD33 CD28 OX40 DAP10 CD33 CD28OX40 DAP12 CD33 CD28 OX40 CD32 CD33 CD28 OX40 CD79a CD33 CD28 OX40 CD79bCD33 CD28 DAP10 CD8 CD33 CD28 DAP10 CD3ζ CD33 CD28 DAP10 CD3δ CD33 CD28DAP10 CD3γ CD33 CD28 DAP10 CD3ε CD33 CD28 DAP10 FcγRI-γ CD33 CD28 DAP10FcγRIII-γ CD33 CD28 DAP10 FcεRIβ CD33 CD28 DAP10 FcεRIγ CD33 CD28 DAP10DAP10 CD33 CD28 DAP10 DAP12 CD33 CD28 DAP10 CD32 CD33 CD28 DAP10 CD79aCD33 CD28 DAP10 CD79b CD33 CD28 DAP12 CD8 CD33 CD28 DAP12 CD3ζ CD33 CD28DAP12 CD3δ CD33 CD28 DAP12 CD3γ CD33 CD28 DAP12 CD3ε CD33 CD28 DAP12FcγRI-γ CD33 CD28 DAP12 FcγRIII-γ CD33 CD28 DAP12 FcεRIβ CD33 CD28 DAP12FcεRIγ CD33 CD28 DAP12 DAP10 CD33 CD28 DAP12 DAP12 CD33 CD28 DAP12 CD32CD33 CD28 DAP12 CD79a CD33 CD28 DAP12 CD79b CD33 CD28 MyD88 CD8 CD33CD28 MyD88 CD3ζ CD33 CD28 MyD88 CD3δ CD33 CD28 MyD88 CD3γ CD33 CD28MyD88 CD3ε CD33 CD28 MyD88 FcγRI-γ CD33 CD28 MyD88 FcγRIII-γ CD33 CD28MyD88 FcεRIβ CD33 CD28 MyD88 FcεRIγ CD33 CD28 MyD88 DAP10 CD33 CD28MyD88 DAP12 CD33 CD28 MyD88 CD32 CD33 CD28 MyD88 CD79a CD33 CD28 MyD88CD79b CD33 CD28 CD7 CD8 CD33 CD28 CD7 CD3ζ CD33 CD28 CD7 CD3δ CD33 CD28CD7 CD3γ CD33 CD28 CD7 CD3ε CD33 CD28 CD7 FcγRI-γ CD33 CD28 CD7FcγRIII-γ CD33 CD28 CD7 FcεRIβ CD33 CD28 CD7 FcεRIγ CD33 CD28 CD7 DAP10CD33 CD28 CD7 DAP12 CD33 CD28 CD7 CD32 CD33 CD28 CD7 CD79a CD33 CD28 CD7CD79b CD33 CD28 BTNL3 CD8 CD33 CD28 BTNL3 CD3ζ CD33 CD28 BTNL3 CD3δ CD33CD28 BTNL3 CD3γ CD33 CD28 BTNL3 CD3ε CD33 CD28 BTNL3 FcγRI-γ CD33 CD28BTNL3 FcγRIII-γ CD33 CD28 BTNL3 FcεRIβ CD33 CD28 BTNL3 FcεRIγ CD33 CD28BTNL3 DAP10 CD33 CD28 BTNL3 DAP12 CD33 CD28 BTNL3 CD32 CD33 CD28 BTNL3CD79a CD33 CD28 BTNL3 CD79b CD33 CD28 NKG2D CD8 CD33 CD28 NKG2D CD3ζCD33 CD28 NKG2D CD3δ CD33 CD28 NKG2D CD3γ CD33 CD28 NKG2D CD3ε CD33 CD28NKG2D FcγRI-γ CD33 CD28 NKG2D FcγRIII-γ CD33 CD28 NKG2D FcεRIβ CD33 CD28NKG2D FcεRIγ CD33 CD28 NKG2D DAP10 CD33 CD28 NKG2D DAP12 CD33 CD28 NKG2DCD32 CD33 CD28 NKG2D CD79a CD33 CD28 NKG2D CD79b CD33 CD8 CD28 CD8 CD33CD8 CD28 CD3ζ CD33 CD8 CD28 CD3δ CD33 CD8 CD28 CD3γ CD33 CD8 CD28 CD3εCD33 CD8 CD28 FcγRI-γ CD33 CD8 CD28 FcγRIII-γ CD33 CD8 CD28 FcεRIβ CD33CD8 CD28 FcεRIγ CD33 CD8 CD28 DAP10 CD33 CD8 CD28 DAP12 CD33 CD8 CD28CD32 CD33 CD8 CD28 CD79a CD33 CD8 CD28 CD79b CD33 CD8 CD8 CD8 CD33 CD8CD8 CD3ζ CD33 CD8 CD8 CD3δ CD33 CD8 CD8 CD3γ CD33 CD8 CD8 CD3ε CD33 CD8CD8 FcγRI-γ CD33 CD8 CD8 FcγRIII-γ CD33 CD8 CD8 FcεRIβ CD33 CD8 CD8FcεRIγ CD33 CD8 CD8 DAP10 CD33 CD8 CD8 DAP12 CD33 CD8 CD8 CD32 CD33 CD8CD8 CD79a CD33 CD8 CD8 CD79b CD33 CD8 CD4 CD8 CD33 CD8 CD4 CD3ζ CD33 CD8CD4 CD3δ CD33 CD8 CD4 CD3γ CD33 CD8 CD4 CD3ε CD33 CD8 CD4 FcγRI-γ CD33CD8 CD4 FcγRIII-γ CD33 CD8 CD4 FcεRIβ CD33 CD8 CD4 FcεRIγ CD33 CD8 CD4DAP10 CD33 CD8 CD4 DAP12 CD33 CD8 CD4 CD32 CD33 CD8 CD4 CD79a CD33 CD8CD4 CD79b CD33 CD8 b2c CD8 CD33 CD8 b2c CD3ζ CD33 CD8 b2c CD3δ CD33 CD8b2c CD3γ CD33 CD8 b2c CD3ε CD33 CD8 b2c FcγRI-γ CD33 CD8 b2c FcγRIII-γCD33 CD8 b2c FcεRIβ CD33 CD8 b2c FcεRIγ CD33 CD8 b2c DAP10 CD33 CD8 b2cDAP12 CD33 CD8 b2c CD32 CD33 CD8 b2c CD79a CD33 CD8 b2c CD79b CD33 CD8CD137/41BB CD8 CD33 CD8 CD137/41BB CD3ζ CD33 CD8 CD137/41BB CD3δ CD33CD8 CD137/41BB CD3γ CD33 CD8 CD137/41BB CD3ε CD33 CD8 CD137/41BB FcγRI-γCD33 CD8 CD137/41BB FcγRIII-γ CD33 CD8 CD137/41BB FcεRIβ CD33 CD8CD137/41BB FcεRIγ CD33 CD8 CD137/41BB DAP10 CD33 CD8 CD137/41BB DAP12CD33 CD8 CD137/41BB CD32 CD33 CD8 CD137/41BB CD79a CD33 CD8 CD137/41BBCD79b CD33 CD8 ICOS CD8 CD33 CD8 ICOS CD3ζ CD33 CD8 ICOS CD3δ CD33 CD8ICOS CD3γ CD33 CD8 ICOS CD3ε CD33 CD8 ICOS FcγRI-γ CD33 CD8 ICOSFcγRIII-γ CD33 CD8 ICOS FcεRIβ CD33 CD8 ICOS FcεRIγ CD33 CD8 ICOS DAP10CD33 CD8 ICOS DAP12 CD33 CD8 ICOS CD32 CD33 CD8 ICOS CD79a CD33 CD8 ICOSCD79b CD33 CD8 CD27 CD8 CD33 CD8 CD27 CD3ζ CD33 CD8 CD27 CD3δ CD33 CD8CD27 CD3γ CD33 CD8 CD27 CD3ε CD33 CD8 CD27 FcγRI-γ CD33 CD8 CD27FcγRIII-γ CD33 CD8 CD27 FcεRIβ CD33 CD8 CD27 FcεRIγ CD33 CD8 CD27 DAP10CD33 CD8 CD27 DAP12 CD33 CD8 CD27 CD32 CD33 CD8 CD27 CD79a CD33 CD8 CD27CD79b CD33 CD8 CD28δ CD8 CD33 CD8 CD28δ CD3ζ CD33 CD8 CD28δ CD3δ CD33CD8 CD28δ CD3γ CD33 CD8 CD28δ CD3ε CD33 CD8 CD28δ FcγRI-γ CD33 CD8 CD28δFcγRIII-γ CD33 CD8 CD28δ FcεRIβ CD33 CD8 CD28δ FcεRIγ CD33 CD8 CD28δDAP10 CD33 CD8 CD28δ DAP12 CD33 CD8 CD28δ CD32 CD33 CD8 CD28δ CD79a CD33CD8 CD28δ CD79b CD33 CD8 CD80 CD8 CD33 CD8 CD80 CD3ζ CD33 CD8 CD80 CD3δCD33 CD8 CD80 CD3γ CD33 CD8 CD80 CD3ε CD33 CD8 CD80 FcγRI-γ CD33 CD8CD80 FcγRIII-γ CD33 CD8 CD80 FcεRIβ CD33 CD8 CD80 FcεRIγ CD33 CD8 CD80DAP10 CD33 CD8 CD80 DAP12 CD33 CD8 CD80 CD32 CD33 CD8 CD80 CD79a CD33CD8 CD80 CD79b CD33 CD8 CD86 CD8 CD33 CD8 CD86 CD3ζ CD33 CD8 CD86 CD3δCD33 CD8 CD86 CD3γ CD33 CD8 CD86 CD3ε CD33 CD8 CD86 FcγRI-γ CD33 CD8CD86 FcγRIII-γ CD33 CD8 CD86 FcεRIβ CD33 CD8 CD86 FcεRIγ CD33 CD8 CD86DAP10 CD33 CD8 CD86 DAP12 CD33 CD8 CD86 CD32 CD33 CD8 CD86 CD79a CD33CD8 CD86 CD79b CD33 CD8 OX40 CD8 CD33 CD8 OX40 CD3ζ CD33 CD8 OX40 CD3δCD33 CD8 OX40 CD3γ CD33 CD8 OX40 CD3ε CD33 CD8 OX40 FcγRI-γ CD33 CD8OX40 FcγRIII-γ CD33 CD8 OX40 FcεRIβ CD33 CD8 OX40 FcεRIγ CD33 CD8 OX40DAP10 CD33 CD8 OX40 DAP12 CD33 CD8 OX40 CD32 CD33 CD8 OX40 CD79a CD33CD8 OX40 CD79b CD33 CD8 DAP10 CD8 CD33 CD8 DAP10 CD3ζ CD33 CD8 DAP10CD3δ CD33 CD8 DAP10 CD3γ CD33 CD8 DAP10 CD3ε CD33 CD8 DAP10 FcγRI-γ CD33CD8 DAP10 FcγRIII-γ CD33 CD8 DAP10 FcεRIβ CD33 CD8 DAP10 FcεRIγ CD33 CD8DAP10 DAP10 CD33 CD8 DAP10 DAP12 CD33 CD8 DAP10 CD32 CD33 CD8 DAP10CD79a CD33 CD8 DAP10 CD79b CD33 CD8 DAP12 CD8 CD33 CD8 DAP12 CD3ζ CD33CD8 DAP12 CD3δ CD33 CD8 DAP12 CD3γ CD33 CD8 DAP12 CD3ε CD33 CD8 DAP12FcγRI-γ CD33 CD8 DAP12 FcγRIII-γ CD33 CD8 DAP12 FcεRIβ CD33 CD8 DAP12FcεRIγ CD33 CD8 DAP12 DAP10 CD33 CD8 DAP12 DAP12 CD33 CD8 DAP12 CD32CD33 CD8 DAP12 CD79a CD33 CD8 DAP12 CD79b CD33 CD8 MyD88 CD8 CD33 CD8MyD88 CD3ζ CD33 CD8 MyD88 CD3δ CD33 CD8 MyD88 CD3γ CD33 CD8 MyD88 CD3εCD33 CD8 MyD88 FcγRI-γ CD33 CD8 MyD88 FcγRIII-γ CD33 CD8 MyD88 FcεRIβCD33 CD8 MyD88 FcεRIγ CD33 CD8 MyD88 DAP10 CD33 CD8 MyD88 DAP12 CD33 CD8MyD88 CD32 CD33 CD8 MyD88 CD79a CD33 CD8 MyD88 CD79b CD33 CD8 CD7 CD8CD33 CD8 CD7 CD3ζ CD33 CD8 CD7 CD3δ CD33 CD8 CD7 CD3γ CD33 CD8 CD7 CD3εCD33 CD8 CD7 FcγRI-γ CD33 CD8 CD7 FcγRIII-γ CD33 CD8 CD7 FcεRIβ CD33 CD8CD7 FcεRIγ CD33 CD8 CD7 DAP10 CD33 CD8 CD7 DAP12 CD33 CD8 CD7 CD32 CD33CD8 CD7 CD79a CD33 CD8 CD7 CD79b CD33 CD8 BTNL3 CD8 CD33 CD8 BTNL3 CD3ζCD33 CD8 BTNL3 CD3δ CD33 CD8 BTNL3 CD3γ CD33 CD8 BTNL3 CD3ε CD33 CD8BTNL3 FcγRI-γ CD33 CD8 BTNL3 FcγRIII-γ CD33 CD8 BTNL3 FcεRIβ CD33 CD8BTNL3 FcεRIγ CD33 CD8 BTNL3 DAP10 CD33 CD8 BTNL3 DAP12 CD33 CD8 BTNL3CD32 CD33 CD8 BTNL3 CD79a CD33 CD8 BTNL3 CD79b CD33 CD8 NKG2D CD8 CD33CD8 NKG2D CD3ζ CD33 CD8 NKG2D CD3δ CD33 CD8 NKG2D CD3γ CD33 CD8 NKG2DCD3ε CD33 CD8 NKG2D FcγRI-γ CD33 CD8 NKG2D FcγRIII-γ CD33 CD8 NKG2DFcεRIβ CD33 CD8 NKG2D FcεRIγ CD33 CD8 NKG2D DAP10 CD33 CD8 NKG2D DAP12CD33 CD8 NKG2D CD32 CD33 CD8 NKG2D CD79a CD33 CD8 NKG2D CD79b CD33 CD4CD28 CD8 CD33 CD4 CD28 CD3ζ CD33 CD4 CD28 CD3δ CD33 CD4 CD28 CD3γ CD33CD4 CD28 CD3ε CD33 CD4 CD28 FcγRI-γ CD33 CD4 CD28 FcγRIII-γ CD33 CD4CD28 FcεRIβ CD33 CD4 CD28 FcεRIγ CD33 CD4 CD28 DAP10 CD33 CD4 CD28 DAP12CD33 CD4 CD28 CD32 CD33 CD4 CD28 CD79a CD33 CD4 CD28 CD79b CD33 CD4 CD8CD8 CD33 CD4 CD8 CD3ζ CD33 CD4 CD8 CD3δ CD33 CD4 CD8 CD3γ CD33 CD4 CD8CD3ε CD33 CD4 CD8 FcγRI-γ CD33 CD4 CD8 FcγRIII-γ CD33 CD4 CD8 FcεRIβCD33 CD4 CD8 FcεRIγ CD33 CD4 CD8 DAP10 CD33 CD4 CD8 DAP12 CD33 CD4 CD8CD32 CD33 CD4 CD8 CD79a CD33 CD4 CD8 CD79b CD33 CD4 CD4 CD8 CD33 CD4 CD4CD3ζ CD33 CD4 CD4 CD3δ CD33 CD4 CD4 CD3γ CD33 CD4 CD4 CD3ε CD33 CD4 CD4FcγRI-γ CD33 CD4 CD4 FcγRIII-γ CD33 CD4 CD4 FcεRIβ CD33 CD4 CD4 FcεRIγCD33 CD4 CD4 DAP10 CD33 CD4 CD4 DAP12 CD33 CD4 CD4 CD32 CD33 CD4 CD4CD79a CD33 CD4 CD4 CD79b CD33 CD4 b2c CD8 CD33 CD4 b2c CD3ζ CD33 CD4 b2cCD3δ CD33 CD4 b2c CD3γ CD33 CD4 b2c CD3ε CD33 CD4 b2c FcγRI-γ CD33 CD4b2c FcγRIII-γ CD33 CD4 b2c FcεRIβ CD33 CD4 b2c FcεRIγ CD33 CD4 b2c DAP10CD33 CD4 b2c DAP12 CD33 CD4 b2c CD32 CD33 CD4 b2c CD79a CD33 CD4 b2cCD79b CD33 CD4 CD137/41BB CD8 CD33 CD4 CD137/41BB CD3ζ CD33 CD4CD137/41BB CD3δ CD33 CD4 CD137/41BB CD3γ CD33 CD4 CD137/41BB CD3ε CD33CD4 CD137/41BB FcγRI-γ CD33 CD4 CD137/41BB FcγRIII-γ CD33 CD4 CD137/41BBFcεRIβ CD33 CD4 CD137/41BB FcεRIγ CD33 CD4 CD137/41BB DAP10 CD33 CD4CD137/41BB DAP12 CD33 CD4 CD137/41BB CD32 CD33 CD4 CD137/41BB CD79a CD33CD4 CD137/41BB CD79b CD33 CD4 ICOS CD8 CD33 CD4 ICOS CD3ζ CD33 CD4 ICOSCD3δ CD33 CD4 ICOS CD3γ CD33 CD4 ICOS CD3ε CD33 CD4 ICOS FcγRI-γ CD33CD4 ICOS FcγRIII-γ CD33 CD4 ICOS FcεRIβ CD33 CD4 ICOS FcεRIγ CD33 CD4ICOS DAP10 CD33 CD4 ICOS DAP12 CD33 CD4 ICOS CD32 CD33 CD4 ICOS CD79aCD33 CD4 ICOS CD79b CD33 CD4 CD27 CD8 CD33 CD4 CD27 CD3ζ CD33 CD4 CD27CD3δ CD33 CD4 CD27 CD3γ CD33 CD4 CD27 CD3ε CD33 CD4 CD27 FcγRI-γ CD33CD4 CD27 FcγRIII-γ CD33 CD4 CD27 FcεRIβ CD33 CD4 CD27 FcεRIγ CD33 CD4CD27 DAP10 CD33 CD4 CD27 DAP12 CD33 CD4 CD27 CD32 CD33 CD4 CD27 CD79aCD33 CD4 CD27 CD79b CD33 CD4 CD28δ CD8 CD33 CD4 CD28δ CD3ζ CD33 CD4CD28δ CD3δ CD33 CD4 CD28δ CD3γ CD33 CD4 CD28δ CD3ε CD33 CD4 CD28δFcγRI-γ CD33 CD4 CD28δ FcγRIII-γ CD33 CD4 CD28δ FcεRIβ CD33 CD4 CD28δFcεRIγ CD33 CD4 CD28δ DAP10 CD33 CD4 CD28δ DAP12 CD33 CD4 CD28δ CD32CD33 CD4 CD28δ CD79a CD33 CD4 CD28δ CD79b CD33 CD4 CD80 CD8 CD33 CD4CD80 CD3ζ CD33 CD4 CD80 CD3δ CD33 CD4 CD80 CD3γ CD33 CD4 CD80 CD3ε CD33CD4 CD80 FcγRI-γ CD33 CD4 CD80 FcγRIII-γ CD33 CD4 CD80 FcεRIβ CD33 CD4CD80 FcεRIγ CD33 CD4 CD80 DAP10 CD33 CD4 CD80 DAP12 CD33 CD4 CD80 CD32CD33 CD4 CD80 CD79a CD33 CD4 CD80 CD79b CD33 CD4 CD86 CD8 CD33 CD4 CD86CD3ζ CD33 CD4 CD86 CD3δ CD33 CD4 CD86 CD3γ CD33 CD4 CD86 CD3ε CD33 CD4CD86 FcγRI-γ CD33 CD4 CD86 FcγRIII-γ CD33 CD4 CD86 FcεRIβ CD33 CD4 CD86FcεRIγ CD33 CD4 CD86 DAP10 CD33 CD4 CD86 DAP12 CD33 CD4 CD86 CD32 CD33CD4 CD86 CD79a CD33 CD4 CD86 CD79b CD33 CD4 OX40 CD8 CD33 CD4 OX40 CD3ζCD33 CD4 OX40 CD3δ CD33 CD4 OX40 CD3γ CD33 CD4 OX40 CD3ε CD33 CD4 OX40FcγRI-γ CD33 CD4 OX40 FcγRIII-γ CD33 CD4 OX40 FcεRIβ CD33 CD4 OX40FcεRIγ CD33 CD4 OX40 DAP10 CD33 CD4 OX40 DAP12 CD33 CD4 OX40 CD32 CD33CD4 OX40 CD79a CD33 CD4 OX40 CD79b CD33 CD4 DAP10 CD8 CD33 CD4 DAP10CD3ζ CD33 CD4 DAP10 CD3δ CD33 CD4 DAP10 CD3γ CD33 CD4 DAP10 CD3ε CD33CD4 DAP10 FcγRI-γ CD33 CD4 DAP10 FcγRIII-γ CD33 CD4 DAP10 FcεRIβ CD33CD4 DAP10 FcεRIγ CD33 CD4 DAP10 DAP10 CD33 CD4 DAP10 DAP12 CD33 CD4DAP10 CD32 CD33 CD4 DAP10 CD79a CD33 CD4 DAP10 CD79b CD33 CD4 DAP12 CD8CD33 CD4 DAP12 CD3ζ CD33 CD4 DAP12 CD3δ CD33 CD4 DAP12 CD3γ CD33 CD4DAP12 CD3ε CD33 CD4 DAP12 FcγRI-γ CD33 CD4 DAP12 FcγRIII-γ CD33 CD4DAP12 FcεRIβ CD33 CD4 DAP12 FcεRIγ CD33 CD4 DAP12 DAP10 CD33 CD4 DAP12DAP12 CD33 CD4 DAP12 CD32 CD33 CD4 DAP12 CD79a CD33 CD4 DAP12 CD79b CD33CD4 MyD88 CD8 CD33 CD4 MyD88 CD3ζ CD33 CD4 MyD88 CD3δ CD33 CD4 MyD88CD3γ CD33 CD4 MyD88 CD3ε CD33 CD4 MyD88 FcγRI-γ CD33 CD4 MyD88 FcγRIII-γCD33 CD4 MyD88 FcεRIβ CD33 CD4 MyD88 FcεRIγ CD33 CD4 MyD88 DAP10 CD33CD4 MyD88 DAP12 CD33 CD4 MyD88 CD32 CD33 CD4 MyD88 CD79a CD33 CD4 MyD88CD79b CD33 CD4 CD7 CD8 CD33 CD4 CD7 CD3ζ CD33 CD4 CD7 CD3δ CD33 CD4 CD7CD3γ CD33 CD4 CD7 CD3ε CD33 CD4 CD7 FcγRI-γ CD33 CD4 CD7 FcγRIII-γ CD33CD4 CD7 FcεRIβ CD33 CD4 CD7 FcεRIγ CD33 CD4 CD7 DAP10 CD33 CD4 CD7 DAP12CD33 CD4 CD7 CD32 CD33 CD4 CD7 CD79a CD33 CD4 CD7 CD79b CD33 CD4 BTNL3CD8 CD33 CD4 BTNL3 CD3ζ CD33 CD4 BTNL3 CD3δ CD33 CD4 BTNL3 CD3γ CD33 CD4BTNL3 CD3ε CD33 CD4 BTNL3 FcγRI-γ CD33 CD4 BTNL3 FcγRIII-γ CD33 CD4BTNL3 FcεRIβ CD33 CD4 BTNL3 FcεRIγ CD33 CD4 BTNL3 DAP10 CD33 CD4 BTNL3DAP12 CD33 CD4 BTNL3 CD32 CD33 CD4 BTNL3 CD79a CD33 CD4 BTNL3 CD79b CD33CD4 NKG2D CD8 CD33 CD4 NKG2D CD3ζ CD33 CD4 NKG2D CD3δ CD33 CD4 NKG2DCD3γ CD33 CD4 NKG2D CD3ε CD33 CD4 NKG2D FcγRI-γ CD33 CD4 NKG2D FcγRIII-γCD33 CD4 NKG2D FcεRIβ CD33 CD4 NKG2D FcεRIγ CD33 CD4 NKG2D DAP10 CD33CD4 NKG2D DAP12 CD33 CD4 NKG2D CD32 CD33 CD4 NKG2D CD79a CD33 CD4 NKG2DCD79b CD33 b2c CD28 CD8 CD33 b2c CD28 CD3ζ CD33 b2c CD28 CD3δ CD33 b2cCD28 CD3γ CD33 b2c CD28 CD3ε CD33 b2c CD28 FcγRI-γ CD33 b2c CD28FcγRIII-γ CD33 b2c CD28 FcεRIβ CD33 b2c CD28 FcεRIγ CD33 b2c CD28 DAP10CD33 b2c CD28 DAP12 CD33 b2c CD28 CD32 CD33 b2c CD28 CD79a CD33 b2c CD28CD79b CD33 b2c CD8 CD8 CD33 b2c CD8 CD3ζ CD33 b2c CD8 CD3δ CD33 b2c CD8CD3γ CD33 b2c CD8 CD3ε CD33 b2c CD8 FcγRI-γ CD33 b2c CD8 FcγRIII-γ CD33b2c CD8 FcεRIβ CD33 b2c CD8 FcεRIγ CD33 b2c CD8 DAP10 CD33 b2c CD8 DAP12CD33 b2c CD8 CD32 CD33 b2c CD8 CD79a CD33 b2c CD8 CD79b CD33 b2c CD4 CD8CD33 b2c CD4 CD3ζ CD33 b2c CD4 CD3δ CD33 b2c CD4 CD3γ CD33 b2c CD4 CD3εCD33 b2c CD4 FcγRI-γ CD33 b2c CD4 FcγRIII-γ CD33 b2c CD4 FcεRIβ CD33 b2cCD4 FcεRIγ CD33 b2c CD4 DAP10 CD33 b2c CD4 DAP12 CD33 b2c CD4 CD32 CD33b2c CD4 CD79a CD33 b2c CD4 CD79b CD33 b2c b2c CD8 CD33 b2c b2c CD3ζ CD33b2c b2c CD3δ CD33 b2c b2c CD3γ CD33 b2c b2c CD3ε CD33 b2c b2c FcγRI-γCD33 b2c b2c FcγRIII-γ CD33 b2c b2c FcεRIβ CD33 b2c b2c FcεRIγ CD33 b2cb2c DAP10 CD33 b2c b2c DAP12 CD33 b2c b2c CD32 CD33 b2c b2c CD79a CD33b2c b2c CD79b CD33 b2c CD137/41BB CD8 CD33 b2c CD137/41BB CD3ζ CD33 b2cCD137/41BB CD3δ CD33 b2c CD137/41BB CD3γ CD33 b2c CD137/41BB CD3ε CD33b2c CD137/41BB FcγRI-γ CD33 b2c CD137/41BB FcγRIII-γ CD33 b2c CD137/41BBFcεRIβ CD33 b2c CD137/41BB FcεRIγ CD33 b2c CD137/41BB DAP10 CD33 b2cCD137/41BB DAP12 CD33 b2c CD137/41BB CD32 CD33 b2c CD137/41BB CD79a CD33b2c CD137/41BB CD79b CD33 b2c ICOS CD8 CD33 b2c ICOS CD3ζ CD33 b2c ICOSCD3δ CD33 b2c ICOS CD3γ CD33 b2c ICOS CD3ε CD33 b2c ICOS FcγRI-γ CD33b2c ICOS FcγRIII-γ CD33 b2c ICOS FcεRIβ CD33 b2c ICOS FcεRIγ CD33 b2cICOS DAP10 CD33 b2c ICOS DAP12 CD33 b2c ICOS CD32 CD33 b2c ICOS CD79aCD33 b2c ICOS CD79b CD33 b2c CD27 CD8 CD33 b2c CD27 CD3ζ CD33 b2c CD27CD3δ CD33 b2c CD27 CD3γ CD33 b2c CD27 CD3ε CD33 b2c CD27 FcγRI-γ CD33b2c CD27 FcγRIII-γ CD33 b2c CD27 FcεRIβ CD33 b2c CD27 FcεRIγ CD33 b2cCD27 DAP10 CD33 b2c CD27 DAP12 CD33 b2c CD27 CD32 CD33 b2c CD27 CD79aCD33 b2c CD27 CD79b CD33 b2c CD28δ CD8 CD33 b2c CD28δ CD3ζ CD33 b2cCD28δ CD3δ CD33 b2c CD28δ CD3γ CD33 b2c CD28δ CD3ε CD33 b2c CD28δFcγRI-γ CD33 b2c CD28δ FcγRIII-γ CD33 b2c CD28δ FcεRIβ CD33 b2c CD28δFcεRIγ CD33 b2c CD28δ DAP10 CD33 b2c CD28δ DAP12 CD33 b2c CD28δ CD32CD33 b2c CD28δ CD79a CD33 b2c CD28δ CD79b CD33 b2c CD80 CD8 CD33 b2cCD80 CD3ζ CD33 b2c CD80 CD3δ CD33 b2c CD80 CD3γ CD33 b2c CD80 CD3ε CD33b2c CD80 FcγRI-γ CD33 b2c CD80 FcγRIII-γ CD33 b2c CD80 FcεRIβ CD33 b2cCD80 FcεRIγ CD33 b2c CD80 DAP10 CD33 b2c CD80 DAP12 CD33 b2c CD80 CD32CD33 b2c CD80 CD79a CD33 b2c CD80 CD79b CD33 b2c CD86 CD8 CD33 b2c CD86CD3ζ CD33 b2c CD86 CD3δ CD33 b2c CD86 CD3γ CD33 b2c CD86 CD3ε CD33 b2cCD86 FcγRI-γ CD33 b2c CD86 FcγRIII-γ CD33 b2c CD86 FcεRIβ CD33 b2c CD86FcεRIγ CD33 b2c CD86 DAP10 CD33 b2c CD86 DAP12 CD33 b2c CD86 CD32 CD33b2c CD86 CD79a CD33 b2c CD86 CD79b CD33 b2c OX40 CD8 CD33 b2c OX40 CD3ζCD33 b2c OX40 CD3δ CD33 b2c OX40 CD3γ CD33 b2c OX40 CD3ε CD33 b2c OX40FcγRI-γ CD33 b2c OX40 FcγRIII-γ CD33 b2c OX40 FcεRIβ CD33 b2c OX40FcεRIγ CD33 b2c OX40 DAP10 CD33 b2c OX40 DAP12 CD33 b2c OX40 CD32 CD33b2c OX40 CD79a CD33 b2c OX40 CD79b CD33 b2c DAP10 CD8 CD33 b2c DAP10CD3ζ CD33 b2c DAP10 CD3δ CD33 b2c DAP10 CD3γ CD33 b2c DAP10 CD3ε CD33b2c DAP10 FcγRI-γ CD33 b2c DAP10 FcγRIII-γ CD33 b2c DAP10 FcεRIβ CD33b2c DAP10 FcεRIγ CD33 b2c DAP10 DAP10 CD33 b2c DAP10 DAP12 CD33 b2cDAP10 CD32 CD33 b2c DAP10 CD79a CD33 b2c DAP10 CD79b CD33 b2c DAP12 CD8CD33 b2c DAP12 CD3ζ CD33 b2c DAP12 CD3δ CD33 b2c DAP12 CD3γ CD33 b2cDAP12 CD3ε CD33 b2c DAP12 FcγRI-γ CD33 b2c DAP12 FcγRIII-γ CD33 b2cDAP12 FcεRIβ CD33 b2c DAP12 FcεRIγ CD33 b2c DAP12 DAP10 CD33 b2c DAP12DAP12 CD33 b2c DAP12 CD32 CD33 b2c DAP12 CD79a CD33 b2c DAP12 CD79b CD33b2c MyD88 CD8 CD33 b2c MyD88 CD3ζ CD33 b2c MyD88 CD3δ CD33 b2c MyD88CD3γ CD33 b2c MyD88 CD3ε CD33 b2c MyD88 FcγRI-γ CD33 b2c MyD88 FcγRIII-γCD33 b2c MyD88 FcεRIβ CD33 b2c MyD88 FcεRIγ CD33 b2c MyD88 DAP10 CD33b2c MyD88 DAP12 CD33 b2c MyD88 CD32 CD33 b2c MyD88 CD79a CD33 b2c MyD88CD79b CD33 b2c CD7 CD8 CD33 b2c CD7 CD3ζ CD33 b2c CD7 CD3δ CD33 b2c CD7CD3γ CD33 b2c CD7 CD3ε CD33 b2c CD7 FcγRI-γ CD33 b2c CD7 FcγRIII-γ CD33b2c CD7 FcεRIβ CD33 b2c CD7 FcεRIγ CD33 b2c CD7 DAP10 CD33 b2c CD7 DAP12CD33 b2c CD7 CD32 CD33 b2c CD7 CD79a CD33 b2c CD7 CD79b CD33 b2c BTNL3CD8 CD33 b2c BTNL3 CD3ζ CD33 b2c BTNL3 CD3δ CD33 b2c BTNL3 CD3γ CD33 b2cBTNL3 CD3ε CD33 b2c BTNL3 FcγRI-γ CD33 b2c BTNL3 FcγRIII-γ CD33 b2cBTNL3 FcεRIβ CD33 b2c BTNL3 FcεRIγ CD33 b2c BTNL3 DAP10 CD33 b2c BTNL3DAP12 CD33 b2c BTNL3 CD32 CD33 b2c BTNL3 CD79a CD33 b2c BTNL3 CD79b CD33b2c NKG2D CD8 CD33 b2c NKG2D CD3ζ CD33 b2c NKG2D CD3δ CD33 b2c NKG2DCD3γ CD33 b2c NKG2D CD3ε CD33 b2c NKG2D FcγRI-γ CD33 b2c NKG2D FcγRIII-γCD33 b2c NKG2D FcεRIβ CD33 b2c NKG2D FcεRIγ CD33 b2c NKG2D DAP10 CD33b2c NKG2D DAP12 CD33 b2c NKG2D CD32 CD33 b2c NKG2D CD79a CD33 b2c NKG2DCD79b CD33 CD137/41BB CD28 CD8 CD33 CD137/41BB CD28 CD3ζ CD33 CD137/41BBCD28 CD3δ CD33 CD137/41BB CD28 CD3γ CD33 CD137/41BB CD28 CD3ε CD33CD137/41BB CD28 FcγRI-γ CD33 CD137/41BB CD28 FcγRIII-γ CD33 CD137/41BBCD28 FcεRIβ CD33 CD137/41BB CD28 FcεRIγ CD33 CD137/41BB CD28 DAP10 CD33CD137/41BB CD28 DAP12 CD33 CD137/41BB CD28 CD32 CD33 CD137/41BB CD28CD79a CD33 CD137/41BB CD28 CD79b CD33 CD137/41BB CD8 CD8 CD33 CD137/41BBCD8 CD3ζ CD33 CD137/41BB CD8 CD3δ CD33 CD137/41BB CD8 CD3γ CD33CD137/41BB CD8 CD3ε CD33 CD137/41BB CD8 FcγRI-γ CD33 CD137/41BB CD8FcγRIII-γ CD33 CD137/41BB CD8 FcεRIβ CD33 CD137/41BB CD8 FcεRIγ CD33CD137/41BB CD8 DAP10 CD33 CD137/41BB CD8 DAP12 CD33 CD137/41BB CD8 CD32CD33 CD137/41BB CD8 CD79a CD33 CD137/41BB CD8 CD79b CD33 CD137/41BB CD4CD8 CD33 CD137/41BB CD4 CD3ζ CD33 CD137/41BB CD4 CD3δ CD33 CD137/41BBCD4 CD3γ CD33 CD137/41BB CD4 CD3ε CD33 CD137/41BB CD4 FcγRI-γ CD33CD137/41BB CD4 FcγRIII-γ CD33 CD137/41BB CD4 FcεRIβ CD33 CD137/41BB CD4FcεRIγ CD33 CD137/41BB CD4 DAP10 CD33 CD137/41BB CD4 DAP12 CD33CD137/41BB CD4 CD32 CD33 CD137/41BB CD4 CD79a CD33 CD137/41BB CD4 CD79bCD33 CD137/41BB b2c CD8 CD33 CD137/41BB b2c CD3ζ CD33 CD137/41BB b2cCD3δ CD33 CD137/41BB b2c CD3γ CD33 CD137/41BB b2c CD3ε CD33 CD137/41BBb2c FcγRI-γ CD33 CD137/41BB b2c FcγRIII-γ CD33 CD137/41BB b2c FcεRIβCD33 CD137/41BB b2c FcεRIγ CD33 CD137/41BB b2c DAP10 CD33 CD137/41BB b2cDAP12 CD33 CD137/41BB b2c CD32 CD33 CD137/41BB b2c CD79a CD33 CD137/41BBb2c CD79b CD33 CD137/41BB CD137/41BB CD8 CD33 CD137/41BB CD137/41BB CD3ζCD33 CD137/41BB CD137/41BB CD3δ CD33 CD137/41BB CD137/41BB CD3γ CD33CD137/41BB CD137/41BB CD3ε CD33 CD137/41BB CD137/41BB FcγRI-γ CD33CD137/41BB CD137/41BB FcγRIII-γ CD33 CD137/41BB CD137/41BB FcεRIβ CD33CD137/41BB CD137/41BB FcεRIγ CD33 CD137/41BB CD137/41BB DAP10 CD33CD137/41BB CD137/41BB DAP12 CD33 CD137/41BB CD137/41BB CD32 CD33CD137/41BB CD137/41BB CD79a CD33 CD137/41BB CD137/41BB CD79b CD33CD137/41BB ICOS CD8 CD33 CD137/41BB ICOS CD3ζ CD33 CD137/41BB ICOS CD3δCD33 CD137/41BB ICOS CD3γ CD33 CD137/41BB ICOS CD3ε CD33 CD137/41BB ICOSFcγRI-γ CD33 CD137/41BB ICOS FcγRIII-γ CD33 CD137/41BB ICOS FcεRIβ CD33CD137/41BB ICOS FcεRIγ CD33 CD137/41BB ICOS DAP10 CD33 CD137/41BB ICOSDAP12 CD33 CD137/41BB ICOS CD32 CD33 CD137/41BB ICOS CD79a CD33CD137/41BB ICOS CD79b CD33 CD137/41BB CD27 CD8 CD33 CD137/41BB CD27 CD3ζCD33 CD137/41BB CD27 CD3δ CD33 CD137/41BB CD27 CD3γ CD33 CD137/41BB CD27CD3ε CD33 CD137/41BB CD27 FcγRI-γ CD33 CD137/41BB CD27 FcγRIII-γ CD33CD137/41BB CD27 FcεRIβ CD33 CD137/41BB CD27 FcεRIγ CD33 CD137/41BB CD27DAP10 CD33 CD137/41BB CD27 DAP12 CD33 CD137/41BB CD27 CD32 CD33CD137/41BB CD27 CD79a CD33 CD137/41BB CD27 CD79b CD33 CD137/41BB CD28δCD8 CD33 CD137/41BB CD28δ CD3ζ CD33 CD137/41BB CD28δ CD3δ CD33CD137/41BB CD28δ CD3γ CD33 CD137/41BB CD28δ CD3ε CD33 CD137/41BB CD28δFcγRI-γ CD33 CD137/41BB CD28δ FcγRIII-γ CD33 CD137/41BB CD28δ FcεRIβCD33 CD137/41BB CD28δ FcεRIγ CD33 CD137/41BB CD28δ DAP10 CD33 CD137/41BBCD28δ DAP12 CD33 CD137/41BB CD28δ CD32 CD33 CD137/41BB CD28δ CD79a CD33CD137/41BB CD28δ CD79b CD33 CD137/41BB CD80 CD8 CD33 CD137/41BB CD80CD3ζ CD33 CD137/41BB CD80 CD3δ CD33 CD137/41BB CD80 CD3γ CD33 CD137/41BBCD80 CD3ε CD33 CD137/41BB CD80 FcγRI-γ CD33 CD137/41BB CD80 FcγRIII-γCD33 CD137/41BB CD80 FcεRIβ CD33 CD137/41BB CD80 FcεRIγ CD33 CD137/41BBCD80 DAP10 CD33 CD137/41BB CD80 DAP12 CD33 CD137/41BB CD80 CD32 CD33CD137/41BB CD80 CD79a CD33 CD137/41BB CD80 CD79b CD33 CD137/41BB CD86CD8 CD33 CD137/41BB CD86 CD3ζ CD33 CD137/41BB CD86 CD3δ CD33 CD137/41BBCD86 CD3γ CD33 CD137/41BB CD86 CD3ε CD33 CD137/41BB CD86 FcγRI-γ CD33CD137/41BB CD86 FcγRIII-γ CD33 CD137/41BB CD86 FcεRIβ CD33 CD137/41BBCD86 FcεRIγ CD33 CD137/41BB CD86 DAP10 CD33 CD137/41BB CD86 DAP12 CD33CD137/41BB CD86 CD32 CD33 CD137/41BB CD86 CD79a CD33 CD137/41BB CD86CD79b CD33 CD137/41BB OX40 CD8 CD33 CD137/41BB OX40 CD3ζ CD33 CD137/41BBOX40 CD3δ CD33 CD137/41BB OX40 CD3γ CD33 CD137/41BB OX40 CD3ε CD33CD137/41BB OX40 FcγRI-γ CD33 CD137/41BB OX40 FcγRIII-γ CD33 CD137/41BBOX40 FcεRIβ CD33 CD137/41BB OX40 FcεRIγ CD33 CD137/41BB OX40 DAP10 CD33CD137/41BB OX40 DAP12 CD33 CD137/41BB OX40 CD32 CD33 CD137/41BB OX40CD79a CD33 CD137/41BB OX40 CD79b CD33 CD137/41BB DAP10 CD8 CD33CD137/41BB DAP10 CD3ζ CD33 CD137/41BB DAP10 CD3δ CD33 CD137/41BB DAP10CD3γ CD33 CD137/41BB DAP10 CD3ε CD33 CD137/41BB DAP10 FcγRI-γ CD33CD137/41BB DAP10 FcγRIII-γ CD33 CD137/41BB DAP10 FcεRIβ CD33 CD137/41BBDAP10 FcεRIγ CD33 CD137/41BB DAP10 DAP10 CD33 CD137/41BB DAP10 DAP12CD33 CD137/41BB DAP10 CD32 CD33 CD137/41BB DAP10 CD79a CD33 CD137/41BBDAP10 CD79b CD33 CD137/41BB DAP12 CD8 CD33 CD137/41BB DAP12 CD3ζ CD33CD137/41BB DAP12 CD3δ CD33 CD137/41BB DAP12 CD3γ CD33 CD137/41BB DAP12CD3ε CD33 CD137/41BB DAP12 FcγRI-γ CD33 CD137/41BB DAP12 FcγRIII-γ CD33CD137/41BB DAP12 FcεRIβ CD33 CD137/41BB DAP12 FcεRIγ CD33 CD137/41BBDAP12 DAP10 CD33 CD137/41BB DAP12 DAP12 CD33 CD137/41BB DAP12 CD32 CD33CD137/41BB DAP12 CD79a CD33 CD137/41BB DAP12 CD79b CD33 CD137/41BB MyD88CD8 CD33 CD137/41BB MyD88 CD3ζ CD33 CD137/41BB MyD88 CD3δ CD33CD137/41BB MyD88 CD3γ CD33 CD137/41BB MyD88 CD3ε CD33 CD137/41BB MyD88FcγRI-γ CD33 CD137/41BB MyD88 FcγRIII-γ CD33 CD137/41BB MyD88 FcεRIβCD33 CD137/41BB MyD88 FcεRIγ CD33 CD137/41BB MyD88 DAP10 CD33 CD137/41BBMyD88 DAP12 CD33 CD137/41BB MyD88 CD32 CD33 CD137/41BB MyD88 CD79a CD33CD137/41BB MyD88 CD79b CD33 CD137/41BB CD7 CD8 CD33 CD137/41BB CD7 CD3ζCD33 CD137/41BB CD7 CD3δ CD33 CD137/41BB CD7 CD3γ CD33 CD137/41BB CD7CD3ε CD33 CD137/41BB CD7 FcγRI-γ CD33 CD137/41BB CD7 FcγRIII-γ CD33CD137/41BB CD7 FcεRIβ CD33 CD137/41BB CD7 FcεRIγ CD33 CD137/41BB CD7DAP10 CD33 CD137/41BB CD7 DAP12 CD33 CD137/41BB CD7 CD32 CD33 CD137/41BBCD7 CD79a CD33 CD137/41BB CD7 CD79b CD33 CD137/41BB BTNL3 CD8 CD33CD137/41BB BTNL3 CD3ζ CD33 CD137/41BB BTNL3 CD3δ CD33 CD137/41BB BTNL3CD3γ CD33 CD137/41BB BTNL3 CD3ε CD33 CD137/41BB BTNL3 FcγRI-γ CD33CD137/41BB BTNL3 FcγRIII-γ CD33 CD137/41BB BTNL3 FcεRIβ CD33 CD137/41BBBTNL3 FcεRIγ CD33 CD137/41BB BTNL3 DAP10 CD33 CD137/41BB BTNL3 DAP12CD33 CD137/41BB BTNL3 CD32 CD33 CD137/41BB BTNL3 CD79a CD33 CD137/41BBBTNL3 CD79b CD33 CD137/41BB NKG2D CD8 CD33 CD137/41BB NKG2D CD3ζ CD33CD137/41BB NKG2D CD3δ CD33 CD137/41BB NKG2D CD3γ CD33 CD137/41BB NKG2DCD3ε CD33 CD137/41BB NKG2D FcγRI-γ CD33 CD137/41BB NKG2D FcγRIII-γ CD33CD137/41BB NKG2D FcεRIβ CD33 CD137/41BB NKG2D FcεRIγ CD33 CD137/41BBNKG2D DAP10 CD33 CD137/41BB NKG2D DAP12 CD33 CD137/41BB NKG2D CD32 CD33CD137/41BB NKG2D CD79a CD33 CD137/41BB NKG2D CD79b CD33 ICOS CD28 CD8CD33 ICOS CD28 CD3ζ CD33 ICOS CD28 CD3δ CD33 ICOS CD28 CD3γ CD33 ICOSCD28 CD3ε CD33 ICOS CD28 FcγRI-γ CD33 ICOS CD28 FcγRIII-γ CD33 ICOS CD28FcεRIβ CD33 ICOS CD28 FcεRIγ CD33 ICOS CD28 DAP10 CD33 ICOS CD28 DAP12CD33 ICOS CD28 CD32 CD33 ICOS CD28 CD79a CD33 ICOS CD28 CD79b CD33 ICOSCD8 CD8 CD33 ICOS CD8 CD3ζ CD33 ICOS CD8 CD3δ CD33 ICOS CD8 CD3γ CD33ICOS CD8 CD3ε CD33 ICOS CD8 FcγRI-γ CD33 ICOS CD8 FcγRIII-γ CD33 ICOSCD8 FcεRIβ CD33 ICOS CD8 FcεRIγ CD33 ICOS CD8 DAP10 CD33 ICOS CD8 DAP12CD33 ICOS CD8 CD32 CD33 ICOS CD8 CD79a CD33 ICOS CD8 CD79b CD33 ICOS CD4CD8 CD33 ICOS CD4 CD3ζ CD33 ICOS CD4 CD3δ CD33 ICOS CD4 CD3γ CD33 ICOSCD4 CD3ε CD33 ICOS CD4 FcγRI-γ CD33 ICOS CD4 FcγRIII-γ CD33 ICOS CD4FcεRIβ CD33 ICOS CD4 FcεRIγ CD33 ICOS CD4 DAP10 CD33 ICOS CD4 DAP12 CD33ICOS CD4 CD32 CD33 ICOS CD4 CD79a CD33 ICOS CD4 CD79b CD33 ICOS b2c CD8CD33 ICOS b2c CD3ζ CD33 ICOS b2c CD3δ CD33 ICOS b2c CD3γ CD33 ICOS b2cCD3ε CD33 ICOS b2c FcγRI-γ CD33 ICOS b2c FcγRIII-γ CD33 ICOS b2c FcεRIβCD33 ICOS b2c FcεRIγ CD33 ICOS b2c DAP10 CD33 ICOS b2c DAP12 CD33 ICOSb2c CD32 CD33 ICOS b2c CD79a CD33 ICOS b2c CD79b CD33 ICOS CD137/41BBCD8 CD33 ICOS CD137/41BB CD3ζ CD33 ICOS CD137/41BB CD3δ CD33 ICOSCD137/41BB CD3γ CD33 ICOS CD137/41BB CD3ε CD33 ICOS CD137/41BB FcγRI-γCD33 ICOS CD137/41BB FcγRIII-γ CD33 ICOS CD137/41BB FcεRIβ CD33 ICOSCD137/41BB FcεRIγ CD33 ICOS CD137/41BB DAP10 CD33 ICOS CD137/41BB DAP12CD33 ICOS CD137/41BB CD32 CD33 ICOS CD137/41BB CD79a CD33 ICOSCD137/41BB CD79b CD33 ICOS ICOS CD8 CD33 ICOS ICOS CD3ζ CD33 ICOS ICOSCD3δ CD33 ICOS ICOS CD3γ CD33 ICOS ICOS CD3ε CD33 ICOS ICOS FcγRI-γ CD33ICOS ICOS FcγRIII-γ CD33 ICOS ICOS FcεRIβ CD33 ICOS ICOS FcεRIγ CD33ICOS ICOS DAP10 CD33 ICOS ICOS DAP12 CD33 ICOS ICOS CD32 CD33 ICOS ICOSCD79a CD33 ICOS ICOS CD79b CD33 ICOS CD27 CD8 CD33 ICOS CD27 CD3ζ CD33ICOS CD27 CD3δ CD33 ICOS CD27 CD3γ CD33 ICOS CD27 CD3ε CD33 ICOS CD27FcγRI-γ CD33 ICOS CD27 FcγRIII-γ CD33 ICOS CD27 FcεRIβ CD33 ICOS CD27FcεRIγ CD33 ICOS CD27 DAP10 CD33 ICOS CD27 DAP12 CD33 ICOS CD27 CD32CD33 ICOS CD27 CD79a CD33 ICOS CD27 CD79b CD33 ICOS CD28δ CD8 CD33 ICOSCD28δ CD3ζ CD33 ICOS CD28δ CD3δ CD33 ICOS CD28δ CD3γ CD33 ICOS CD28δCD3ε CD33 ICOS CD28δ FcγRI-γ CD33 ICOS CD28δ FcγRIII-γ CD33 ICOS CD28δFcεRIβ CD33 ICOS CD28δ FcεRIγ CD33 ICOS CD28δ DAP10 CD33 ICOS CD28δDAP12 CD33 ICOS CD28δ CD32 CD33 ICOS CD28δ CD79a CD33 ICOS CD28δ CD79bCD33 ICOS CD80 CD8 CD33 ICOS CD80 CD3ζ CD33 ICOS CD80 CD3δ CD33 ICOSCD80 CD3γ CD33 ICOS CD80 CD3ε CD33 ICOS CD80 FcγRI-γ CD33 ICOS CD80FcγRIII-γ CD33 ICOS CD80 FcεRIβ CD33 ICOS CD80 FcεRIγ CD33 ICOS CD80DAP10 CD33 ICOS CD80 DAP12 CD33 ICOS CD80 CD32 CD33 ICOS CD80 CD79a CD33ICOS CD80 CD79b CD33 ICOS CD86 CD8 CD33 ICOS CD86 CD3ζ CD33 ICOS CD86CD3δ CD33 ICOS CD86 CD3γ CD33 ICOS CD86 CD3ε CD33 ICOS CD86 FcγRI-γ CD33ICOS CD86 FcγRIII-γ CD33 ICOS CD86 FcεRIβ CD33 ICOS CD86 FcεRIγ CD33ICOS CD86 DAP10 CD33 ICOS CD86 DAP12 CD33 ICOS CD86 CD32 CD33 ICOS CD86CD79a CD33 ICOS CD86 CD79b CD33 ICOS OX40 CD8 CD33 ICOS OX40 CD3ζ CD33ICOS OX40 CD3δ CD33 ICOS OX40 CD3γ CD33 ICOS OX40 CD3ε CD33 ICOS OX40FcγRI-γ CD33 ICOS OX40 FcγRIII-γ CD33 ICOS OX40 FcεRIβ CD33 ICOS OX40FcεRIγ CD33 ICOS OX40 DAP10 CD33 ICOS OX40 DAP12 CD33 ICOS OX40 CD32CD33 ICOS OX40 CD79a CD33 ICOS OX40 CD79b CD33 ICOS DAP10 CD8 CD33 ICOSDAP10 CD3ζ CD33 ICOS DAP10 CD3δ CD33 ICOS DAP10 CD3γ CD33 ICOS DAP10CD3ε CD33 ICOS DAP10 FcγRI-γ CD33 ICOS DAP10 FcγRIII-γ CD33 ICOS DAP10FcεRIβ CD33 ICOS DAP10 FcεRIγ CD33 ICOS DAP10 DAP10 CD33 ICOS DAP10DAP12 CD33 ICOS DAP10 CD32 CD33 ICOS DAP10 CD79a CD33 ICOS DAP10 CD79bCD33 ICOS DAP12 CD8 CD33 ICOS DAP12 CD3ζ CD33 ICOS DAP12 CD3δ CD33 ICOSDAP12 CD3γ CD33 ICOS DAP12 CD3ε CD33 ICOS DAP12 FcγRI-γ CD33 ICOS DAP12FcγRIII-γ CD33 ICOS DAP12 FcεRIβ CD33 ICOS DAP12 FcεRIγ CD33 ICOS DAP12DAP10 CD33 ICOS DAP12 DAP12 CD33 ICOS DAP12 CD32 CD33 ICOS DAP12 CD79aCD33 ICOS DAP12 CD79b CD33 ICOS MyD88 CD8 CD33 ICOS MyD88 CD3ζ CD33 ICOSMyD88 CD3δ CD33 ICOS MyD88 CD3γ CD33 ICOS MyD88 CD3ε CD33 ICOS MyD88FcγRI-γ CD33 ICOS MyD88 FcγRIII-γ CD33 ICOS MyD88 FcεRIβ CD33 ICOS MyD88FcεRIγ CD33 ICOS MyD88 DAP10 CD33 ICOS MyD88 DAP12 CD33 ICOS MyD88 CD32CD33 ICOS MyD88 CD79a CD33 ICOS MyD88 CD79b CD33 ICOS CD7 CD8 CD33 ICOSCD7 CD3ζ CD33 ICOS CD7 CD3δ CD33 ICOS CD7 CD3γ CD33 ICOS CD7 CD3ε CD33ICOS CD7 FcγRI-γ CD33 ICOS CD7 FcγRIII-γ CD33 ICOS CD7 FcεRIβ CD33 ICOSCD7 FcεRIγ CD33 ICOS CD7 DAP10 CD33 ICOS CD7 DAP12 CD33 ICOS CD7 CD32CD33 ICOS CD7 CD79a CD33 ICOS CD7 CD79b CD33 ICOS BTNL3 CD8 CD33 ICOSBTNL3 CD3ζ CD33 ICOS BTNL3 CD3δ CD33 ICOS BTNL3 CD3γ CD33 ICOS BTNL3CD3ε CD33 ICOS BTNL3 FcγRI-γ CD33 ICOS BTNL3 FcγRIII-γ CD33 ICOS BTNL3FcεRIβ CD33 ICOS BTNL3 FcεRIγ CD33 ICOS BTNL3 DAP10 CD33 ICOS BTNL3DAP12 CD33 ICOS BTNL3 CD32 CD33 ICOS BTNL3 CD79a CD33 ICOS BTNL3 CD79bCD33 ICOS NKG2D CD8 CD33 ICOS NKG2D CD3ζ CD33 ICOS NKG2D CD3δ CD33 ICOSNKG2D CD3γ CD33 ICOS NKG2D CD3ε CD33 ICOS NKG2D FcγRI-γ CD33 ICOS NKG2DFcγRIII-γ CD33 ICOS NKG2D FcεRIβ CD33 ICOS NKG2D FcεRIγ CD33 ICOS NKG2DDAP10 CD33 ICOS NKG2D DAP12 CD33 ICOS NKG2D CD32 CD33 ICOS NKG2D CD79aCD33 ICOS NKG2D CD79b CD33 CD27 CD28 CD8 CD33 CD27 CD28 CD3ζ CD33 CD27CD28 CD3δ CD33 CD27 CD28 CD3γ CD33 CD27 CD28 CD3ε CD33 CD27 CD28 FcγRI-γCD33 CD27 CD28 FcγRIII-γ CD33 CD27 CD28 FcεRIβ CD33 CD27 CD28 FcεRIγCD33 CD27 CD28 DAP10 CD33 CD27 CD28 DAP12 CD33 CD27 CD28 CD32 CD33 CD27CD28 CD79a CD33 CD27 CD28 CD79b CD33 CD27 CD8 CD8 CD33 CD27 CD8 CD3ζCD33 CD27 CD8 CD3δ CD33 CD27 CD8 CD3γ CD33 CD27 CD8 CD3ε CD33 CD27 CD8FcγRI-γ CD33 CD27 CD8 FcγRIII-γ CD33 CD27 CD8 FcεRIβ CD33 CD27 CD8FcεRIγ CD33 CD27 CD8 DAP10 CD33 CD27 CD8 DAP12 CD33 CD27 CD8 CD32 CD33CD27 CD8 CD79a CD33 CD27 CD8 CD79b CD33 CD27 CD4 CD8 CD33 CD27 CD4 CD3ζCD33 CD27 CD4 CD3δ CD33 CD27 CD4 CD3γ CD33 CD27 CD4 CD3ε CD33 CD27 CD4FcγRI-γ CD33 CD27 CD4 FcγRIII-γ CD33 CD27 CD4 FcεRIβ CD33 CD27 CD4FcεRIγ CD33 CD27 CD4 DAP10 CD33 CD27 CD4 DAP12 CD33 CD27 CD4 CD32 CD33CD27 CD4 CD79a CD33 CD27 CD4 CD79b CD33 CD27 b2c CD8 CD33 CD27 b2c CD3ζCD33 CD27 b2c CD3δ CD33 CD27 b2c CD3γ CD33 CD27 b2c CD3ε CD33 CD27 b2cFcγRI-γ CD33 CD27 b2c FcγRIII-γ CD33 CD27 b2c FcεRIβ CD33 CD27 b2cFcεRIγ CD33 CD27 b2c DAP10 CD33 CD27 b2c DAP12 CD33 CD27 b2c CD32 CD33CD27 b2c CD79a CD33 CD27 b2c CD79b CD33 CD27 CD137/41BB CD8 CD33 CD27CD137/41BB CD3ζ CD33 CD27 CD137/41BB CD3δ CD33 CD27 CD137/41BB CD3γ CD33CD27 CD137/41BB CD3ε CD33 CD27 CD137/41BB FcγRI-γ CD33 CD27 CD137/41BBFcγRIII-γ CD33 CD27 CD137/41BB FcεRIβ CD33 CD27 CD137/41BB FcεRIγ CD33CD27 CD137/41BB DAP10 CD33 CD27 CD137/41BB DAP12 CD33 CD27 CD137/41BBCD32 CD33 CD27 CD137/41BB CD79a CD33 CD27 CD137/41BB CD79b CD33 CD27ICOS CD8 CD33 CD27 ICOS CD3ζ CD33 CD27 ICOS CD3δ CD33 CD27 ICOS CD3γCD33 CD27 ICOS CD3ε CD33 CD27 ICOS FcγRI-γ CD33 CD27 ICOS FcγRIII-γ CD33CD27 ICOS FcεRIβ CD33 CD27 ICOS FcεRIγ CD33 CD27 ICOS DAP10 CD33 CD27ICOS DAP12 CD33 CD27 ICOS CD32 CD33 CD27 ICOS CD79a CD33 CD27 ICOS CD79bCD33 CD27 CD27 CD8 CD33 CD27 CD27 CD3ζ CD33 CD27 CD27 CD3δ CD33 CD27CD27 CD3γ CD33 CD27 CD27 CD3ε CD33 CD27 CD27 FcγRI-γ CD33 CD27 CD27FcγRIII-γ CD33 CD27 CD27 FcεRIβ CD33 CD27 CD27 FcεRIγ CD33 CD27 CD27DAP10 CD33 CD27 CD27 DAP12 CD33 CD27 CD27 CD32 CD33 CD27 CD27 CD79a CD33CD27 CD27 CD79b CD33 CD27 CD28δ CD8 CD33 CD27 CD28δ CD3ζ CD33 CD27 CD28δCD3δ CD33 CD27 CD28δ CD3γ CD33 CD27 CD28δ CD3ε CD33 CD27 CD28δ FcγRI-γCD33 CD27 CD28δ FcγRIII-γ CD33 CD27 CD28δ FcεRIβ CD33 CD27 CD28δ FcεRIγCD33 CD27 CD28δ DAP10 CD33 CD27 CD28δ DAP12 CD33 CD27 CD28δ CD32 CD33CD27 CD28δ CD79a CD33 CD27 CD28δ CD79b CD33 CD27 CD80 CD8 CD33 CD27 CD80CD3ζ CD33 CD27 CD80 CD3δ CD33 CD27 CD80 CD3γ CD33 CD27 CD80 CD3ε CD33CD27 CD80 FcγRI-γ CD33 CD27 CD80 FcγRIII-γ CD33 CD27 CD80 FcεRIβ CD33CD27 CD80 FcεRIγ CD33 CD27 CD80 DAP10 CD33 CD27 CD80 DAP12 CD33 CD27CD80 CD32 CD33 CD27 CD80 CD79a CD33 CD27 CD80 CD79b CD33 CD27 CD86 CD8CD33 CD27 CD86 CD3ζ CD33 CD27 CD86 CD3δ CD33 CD27 CD86 CD3γ CD33 CD27CD86 CD3ε CD33 CD27 CD86 FcγRI-γ CD33 CD27 CD86 FcγRIII-γ CD33 CD27 CD86FcεRIβ CD33 CD27 CD86 FcεRIγ CD33 CD27 CD86 DAP10 CD33 CD27 CD86 DAP12CD33 CD27 CD86 CD32 CD33 CD27 CD86 CD79a CD33 CD27 CD86 CD79b CD33 CD27OX40 CD8 CD33 CD27 OX40 CD3ζ CD33 CD27 OX40 CD3δ CD33 CD27 OX40 CD3γCD33 CD27 OX40 CD3ε CD33 CD27 OX40 FcγRI-γ CD33 CD27 OX40 FcγRIII-γ CD33CD27 OX40 FcεRIβ CD33 CD27 OX40 FcεRIγ CD33 CD27 OX40 DAP10 CD33 CD27OX40 DAP12 CD33 CD27 OX40 CD32 CD33 CD27 OX40 CD79a CD33 CD27 OX40 CD79bCD33 CD27 DAP10 CD8 CD33 CD27 DAP10 CD3ζ CD33 CD27 DAP10 CD3δ CD33 CD27DAP10 CD3γ CD33 CD27 DAP10 CD3ε CD33 CD27 DAP10 FcγRI-γ CD33 CD27 DAP10FcγRIII-γ CD33 CD27 DAP10 FcεRIβ CD33 CD27 DAP10 FcεRIγ CD33 CD27 DAP10DAP10 CD33 CD27 DAP10 DAP12 CD33 CD27 DAP10 CD32 CD33 CD27 DAP10 CD79aCD33 CD27 DAP10 CD79b CD33 CD27 DAP12 CD8 CD33 CD27 DAP12 CD3ζ CD33 CD27DAP12 CD3δ CD33 CD27 DAP12 CD3γ CD33 CD27 DAP12 CD3ε CD33 CD27 DAP12FcγRI-γ CD33 CD27 DAP12 FcγRIII-γ CD33 CD27 DAP12 FcεRIβ CD33 CD27 DAP12FcεRIγ CD33 CD27 DAP12 DAP10 CD33 CD27 DAP12 DAP12 CD33 CD27 DAP12 CD32CD33 CD27 DAP12 CD79a CD33 CD27 DAP12 CD79b CD33 CD27 MyD88 CD8 CD33CD27 MyD88 CD3ζ CD33 CD27 MyD88 CD3δ CD33 CD27 MyD88 CD3γ CD33 CD27MyD88 CD3ε CD33 CD27 MyD88 FcγRI-γ CD33 CD27 MyD88 FcγRIII-γ CD33 CD27MyD88 FcεRIβ CD33 CD27 MyD88 FcεRIγ CD33 CD27 MyD88 DAP10 CD33 CD27MyD88 DAP12 CD33 CD27 MyD88 CD32 CD33 CD27 MyD88 CD79a CD33 CD27 MyD88CD79b CD33 CD27 CD7 CD8 CD33 CD27 CD7 CD3ζ CD33 CD27 CD7 CD3δ CD33 CD27CD7 CD3γ CD33 CD27 CD7 CD3ε CD33 CD27 CD7 FcγRI-γ CD33 CD27 CD7FcγRIII-γ CD33 CD27 CD7 FcεRIβ CD33 CD27 CD7 FcεRIγ CD33 CD27 CD7 DAP10CD33 CD27 CD7 DAP12 CD33 CD27 CD7 CD32 CD33 CD27 CD7 CD79a CD33 CD27 CD7CD79b CD33 CD27 BTNL3 CD8 CD33 CD27 BTNL3 CD3ζ CD33 CD27 BTNL3 CD3δ CD33CD27 BTNL3 CD3γ CD33 CD27 BTNL3 CD3ε CD33 CD27 BTNL3 FcγRI-γ CD33 CD27BTNL3 FcγRIII-γ CD33 CD27 BTNL3 FcεRIβ CD33 CD27 BTNL3 FcεRIγ CD33 CD27BTNL3 DAP10 CD33 CD27 BTNL3 DAP12 CD33 CD27 BTNL3 CD32 CD33 CD27 BTNL3CD79a CD33 CD27 BTNL3 CD79b CD33 CD27 NKG2D CD8 CD33 CD27 NKG2D CD3ζCD33 CD27 NKG2D CD3δ CD33 CD27 NKG2D CD3γ CD33 CD27 NKG2D CD3ε CD33 CD27NKG2D FcγRI-γ CD33 CD27 NKG2D FcγRIII-γ CD33 CD27 NKG2D FcεRIβ CD33 CD27NKG2D FcεRIγ CD33 CD27 NKG2D DAP10 CD33 CD27 NKG2D DAP12 CD33 CD27 NKG2DCD32 CD33 CD27 NKG2D CD79a CD33 CD27 NKG2D CD79b CD33 CD28δ CD28 CD8CD33 CD28δ CD28 CD3ζ CD33 CD28δ CD28 CD3δ CD33 CD28δ CD28 CD3γ CD33CD28δ CD28 CD3ε CD33 CD28δ CD28 FcγRI-γ CD33 CD28δ CD28 FcγRIII-γ CD33CD28δ CD28 FcεRIβ CD33 CD28δ CD28 FcεRIγ CD33 CD28δ CD28 DAP10 CD33CD28δ CD28 DAP12 CD33 CD28δ CD28 CD32 CD33 CD28δ CD28 CD79a CD33 CD28δCD28 CD79b CD33 CD28δ CD8 CD8 CD33 CD28δ CD8 CD3ζ CD33 CD28δ CD8 CD3δCD33 CD28δ CD8 CD3γ CD33 CD28δ CD8 CD3ε CD33 CD28δ CD8 FcγRI-γ CD33CD28δ CD8 FcγRIII-γ CD33 CD28δ CD8 FcεRIβ CD33 CD28δ CD8 FcεRIγ CD33CD28δ CD8 DAP10 CD33 CD28δ CD8 DAP12 CD33 CD28δ CD8 CD32 CD33 CD28δ CD8CD79a CD33 CD28δ CD8 CD79b CD33 CD28δ CD4 CD8 CD33 CD28δ CD4 CD3ζ CD33CD28δ CD4 CD3δ CD33 CD28δ CD4 CD3γ CD33 CD28δ CD4 CD3ε CD33 CD28δ CD4FcγRI-γ CD33 CD28δ CD4 FcγRIII-γ CD33 CD28δ CD4 FcεRIβ CD33 CD28δ CD4FcεRIγ CD33 CD28δ CD4 DAP10 CD33 CD28δ CD4 DAP12 CD33 CD28δ CD4 CD32CD33 CD28δ CD4 CD79a CD33 CD28δ CD4 CD79b CD33 CD28δ b2c CD8 CD33 CD28δb2c CD3ζ CD33 CD28δ b2c CD3δ CD33 CD28δ b2c CD3γ CD33 CD28δ b2c CD3εCD33 CD28δ b2c FcγRI-γ CD33 CD28δ b2c FcγRIII-γ CD33 CD28δ b2c FcεRIβCD33 CD28δ b2c FcεRIγ CD33 CD28δ b2c DAP10 CD33 CD28δ b2c DAP12 CD33CD28δ b2c CD32 CD33 CD28δ b2c CD79a CD33 CD28δ b2c CD79b CD33 CD28δCD137/41BB CD8 CD33 CD28δ CD137/41BB CD3ζ CD33 CD28δ CD137/41BB CD3δCD33 CD28δ CD137/41BB CD3γ CD33 CD28δ CD137/41BB CD3ε CD33 CD28δCD137/41BB FcγRI-γ CD33 CD28δ CD137/41BB FcγRIII-γ CD33 CD28δ CD137/41BBFcεRIβ CD33 CD28δ CD137/41BB FcεRIγ CD33 CD28δ CD137/41BB DAP10 CD33CD28δ CD137/41BB DAP12 CD33 CD28δ CD137/41BB CD32 CD33 CD28δ CD137/41BBCD79a CD33 CD28δ CD137/41BB CD79b CD33 CD28δ ICOS CD8 CD33 CD28δ ICOSCD3ζ CD33 CD28δ ICOS CD3δ CD33 CD28δ ICOS CD3γ CD33 CD28δ ICOS CD3ε CD33CD28δ ICOS FcγRI-γ CD33 CD28δ ICOS FcγRIII-γ CD33 CD28δ ICOS FcεRIβ CD33CD28δ ICOS FcεRIγ CD33 CD28δ ICOS DAP10 CD33 CD28δ ICOS DAP12 CD33 CD28δICOS CD32 CD33 CD28δ ICOS CD79a CD33 CD28δ ICOS CD79b CD33 CD28δ CD27CD8 CD33 CD28δ CD27 CD3ζ CD33 CD28δ CD27 CD3δ CD33 CD28δ CD27 CD3γ CD33CD28δ CD27 CD3ε CD33 CD28δ CD27 FcγRI-γ CD33 CD28δ CD27 FcγRIII-γ CD33CD28δ CD27 FcεRIβ CD33 CD28δ CD27 FcεRIγ CD33 CD28δ CD27 DAP10 CD33CD28δ CD27 DAP12 CD33 CD28δ CD27 CD32 CD33 CD28δ CD27 CD79a CD33 CD28δCD27 CD79b CD33 CD28δ CD28δ CD8 CD33 CD28δ CD28δ CD3ζ CD33 CD28δ CD28δCD3δ CD33 CD28δ CD28δ CD3γ CD33 CD28δ CD28δ CD3ε CD33 CD28δ CD28δFcγRI-γ CD33 CD28δ CD28δ FcγRIII-γ CD33 CD28δ CD28δ FcεRIβ CD33 CD28δCD28δ FcεRIγ CD33 CD28δ CD28δ DAP10 CD33 CD28δ CD28δ DAP12 CD33 CD28δCD28δ CD32 CD33 CD28δ CD28δ CD79a CD33 CD28δ CD28δ CD79b CD33 CD28δ CD80CD8 CD33 CD28δ CD80 CD3ζ CD33 CD28δ CD80 CD3δ CD33 CD28δ CD80 CD3γ CD33CD28δ CD80 CD3ε CD33 CD28δ CD80 FcγRI-γ CD33 CD28δ CD80 FcγRIII-γ CD33CD28δ CD80 FcεRIβ CD33 CD28δ CD80 FcεRIγ CD33 CD28δ CD80 DAP10 CD33CD28δ CD80 DAP12 CD33 CD28δ CD80 CD32 CD33 CD28δ CD80 CD79a CD33 CD28δCD80 CD79b CD33 CD28δ CD86 CD8 CD33 CD28δ CD86 CD3ζ CD33 CD28δ CD86 CD3δCD33 CD28δ CD86 CD3γ CD33 CD28δ CD86 CD3ε CD33 CD28δ CD86 FcγRI-γ CD33CD28δ CD86 FcγRIII-γ CD33 CD28δ CD86 FcεRIβ CD33 CD28δ CD86 FcεRIγ CD33CD28δ CD86 DAP10 CD33 CD28δ CD86 DAP12 CD33 CD28δ CD86 CD32 CD33 CD28δCD86 CD79a CD33 CD28δ CD86 CD79b CD33 CD28δ OX40 CD8 CD33 CD28δ OX40CD3ζ CD33 CD28δ OX40 CD3δ CD33 CD28δ OX40 CD3γ CD33 CD28δ OX40 CD3ε CD33CD28δ OX40 FcγRI-γ CD33 CD28δ OX40 FcγRIII-γ CD33 CD28δ OX40 FcεRIβ CD33CD28δ OX40 FcεRIγ CD33 CD28δ OX40 DAP10 CD33 CD28δ OX40 DAP12 CD33 CD28δOX40 CD32 CD33 CD28δ OX40 CD79a CD33 CD28δ OX40 CD79b CD33 CD28δ DAP10CD8 CD33 CD28δ DAP10 CD3ζ CD33 CD28δ DAP10 CD3δ CD33 CD28δ DAP10 CD3γCD33 CD28δ DAP10 CD3ε CD33 CD28δ DAP10 FcγRI-γ CD33 CD28δ DAP10FcγRIII-γ CD33 CD28δ DAP10 FcεRIβ CD33 CD28δ DAP10 FcεRIγ CD33 CD28δDAP10 DAP10 CD33 CD28δ DAP10 DAP12 CD33 CD28δ DAP10 CD32 CD33 CD28δDAP10 CD79a CD33 CD28δ DAP10 CD79b CD33 CD28δ DAP12 CD8 CD33 CD28δ DAP12CD3ζ CD33 CD28δ DAP12 CD3δ CD33 CD28δ DAP12 CD3γ CD33 CD28δ DAP12 CD3εCD33 CD28δ DAP12 FcγRI-γ CD33 CD28δ DAP12 FcγRIII-γ CD33 CD28δ DAP12FcεRIβ CD33 CD28δ DAP12 FcεRIγ CD33 CD28δ DAP12 DAP10 CD33 CD28δ DAP12DAP12 CD33 CD28δ DAP12 CD32 CD33 CD28δ DAP12 CD79a CD33 CD28δ DAP12CD79b CD33 CD28δ MyD88 CD8 CD33 CD28δ MyD88 CD3ζ CD33 CD28δ MyD88 CD3δCD33 CD28δ MyD88 CD3γ CD33 CD28δ MyD88 CD3ε CD33 CD28δ MyD88 FcγRI-γCD33 CD28δ MyD88 FcγRIII-γ CD33 CD28δ MyD88 FcεRIβ CD33 CD28δ MyD88FcεRIγ CD33 CD28δ MyD88 DAP10 CD33 CD28δ MyD88 DAP12 CD33 CD28δ MyD88CD32 CD33 CD28δ MyD88 CD79a CD33 CD28δ MyD88 CD79b CD33 CD28δ CD7 CD8CD33 CD28δ CD7 CD3ζ CD33 CD28δ CD7 CD3δ CD33 CD28δ CD7 CD3γ CD33 CD28δCD7 CD3ε CD33 CD28δ CD7 FcγRI-γ CD33 CD28δ CD7 FcγRIII-γ CD33 CD28δ CD7FcεRIβ CD33 CD28δ CD7 FcεRIγ CD33 CD28δ CD7 DAP10 CD33 CD28δ CD7 DAP12CD33 CD28δ CD7 CD32 CD33 CD28δ CD7 CD79a CD33 CD28δ CD7 CD79b CD33 CD28δBTNL3 CD8 CD33 CD28δ BTNL3 CD3ζ CD33 CD28δ BTNL3 CD3δ CD33 CD28δ BTNL3CD3γ CD33 CD28δ BTNL3 CD3ε CD33 CD28δ BTNL3 FcγRI-γ CD33 CD28δ BTNL3FcγRIII-γ CD33 CD28δ BTNL3 FcεRIβ CD33 CD28δ BTNL3 FcεRIγ CD33 CD28δBTNL3 DAP10 CD33 CD28δ BTNL3 DAP12 CD33 CD28δ BTNL3 CD32 CD33 CD28δBTNL3 CD79a CD33 CD28δ BTNL3 CD79b CD33 CD28δ NKG2D CD8 CD33 CD28δ NKG2DCD3ζ CD33 CD28δ NKG2D CD3δ CD33 CD28δ NKG2D CD3γ CD33 CD28δ NKG2D CD3εCD33 CD28δ NKG2D FcγRI-γ CD33 CD28δ NKG2D FcγRIII-γ CD33 CD28δ NKG2DFcεRIβ CD33 CD28δ NKG2D FcεRIγ CD33 CD28δ NKG2D DAP10 CD33 CD28δ NKG2DDAP12 CD33 CD28δ NKG2D CD32 CD33 CD28δ NKG2D CD79a CD33 CD28δ NKG2DCD79b CD33 CD80 CD28 CD8 CD33 CD80 CD28 CD3ζ CD33 CD80 CD28 CD3δ CD33CD80 CD28 CD3γ CD33 CD80 CD28 CD3ε CD33 CD80 CD28 FcγRI-γ CD33 CD80 CD28FcγRIII-γ CD33 CD80 CD28 FcεRIβ CD33 CD80 CD28 FcεRIγ CD33 CD80 CD28DAP10 CD33 CD80 CD28 DAP12 CD33 CD80 CD28 CD32 CD33 CD80 CD28 CD79a CD33CD80 CD28 CD79b CD33 CD80 CD8 CD8 CD33 CD80 CD8 CD3ζ CD33 CD80 CD8 CD3δCD33 CD80 CD8 CD3γ CD33 CD80 CD8 CD3ε CD33 CD80 CD8 FcγRI-γ CD33 CD80CD8 FcγRIII-γ CD33 CD80 CD8 FcεRIβ CD33 CD80 CD8 FcεRIγ CD33 CD80 CD8DAP10 CD33 CD80 CD8 DAP12 CD33 CD80 CD8 CD32 CD33 CD80 CD8 CD79a CD33CD80 CD8 CD79b CD33 CD80 CD4 CD8 CD33 CD80 CD4 CD3ζ CD33 CD80 CD4 CD3δCD33 CD80 CD4 CD3γ CD33 CD80 CD4 CD3ε CD33 CD80 CD4 FcγRI-γ CD33 CD80CD4 FcγRIII-γ CD33 CD80 CD4 FcεRIβ CD33 CD80 CD4 FcεRIγ CD33 CD80 CD4DAP10 CD33 CD80 CD4 DAP12 CD33 CD80 CD4 CD32 CD33 CD80 CD4 CD79a CD33CD80 CD4 CD79b CD33 CD80 b2c CD8 CD33 CD80 b2c CD3ζ CD33 CD80 b2c CD3δCD33 CD80 b2c CD3γ CD33 CD80 b2c CD3ε CD33 CD80 b2c FcγRI-γ CD33 CD80b2c FcγRIII-γ CD33 CD80 b2c FcεRIβ CD33 CD80 b2c FcεRIγ CD33 CD80 b2cDAP10 CD33 CD80 b2c DAP12 CD33 CD80 b2c CD32 CD33 CD80 b2c CD79a CD33CD80 b2c CD79b CD33 CD80 CD137/41BB CD8 CD33 CD80 CD137/41BB CD3ζ CD33CD80 CD137/41BB CD3δ CD33 CD80 CD137/41BB CD3γ CD33 CD80 CD137/41BB CD3εCD33 CD80 CD137/41BB FcγRI-γ CD33 CD80 CD137/41BB FcγRIII-γ CD33 CD80CD137/41BB FcεRIβ CD33 CD80 CD137/41BB FcεRIγ CD33 CD80 CD137/41BB DAP10CD33 CD80 CD137/41BB DAP12 CD33 CD80 CD137/41BB CD32 CD33 CD80CD137/41BB CD79a CD33 CD80 CD137/41BB CD79b CD33 CD80 ICOS CD8 CD33 CD80ICOS CD3ζ CD33 CD80 ICOS CD3δ CD33 CD80 ICOS CD3γ CD33 CD80 ICOS CD3εCD33 CD80 ICOS FcγRI-γ CD33 CD80 ICOS FcγRIII-γ CD33 CD80 ICOS FcεRIβCD33 CD80 ICOS FcεRIγ CD33 CD80 ICOS DAP10 CD33 CD80 ICOS DAP12 CD33CD80 ICOS CD32 CD33 CD80 ICOS CD79a CD33 CD80 ICOS CD79b CD33 CD80 CD27CD8 CD33 CD80 CD27 CD3ζ CD33 CD80 CD27 CD3δ CD33 CD80 CD27 CD3γ CD33CD80 CD27 CD3ε CD33 CD80 CD27 FcγRI-γ CD33 CD80 CD27 FcγRIII-γ CD33 CD80CD27 FcεRIβ CD33 CD80 CD27 FcεRIγ CD33 CD80 CD27 DAP10 CD33 CD80 CD27DAP12 CD33 CD80 CD27 CD32 CD33 CD80 CD27 CD79a CD33 CD80 CD27 CD79b CD33CD80 CD28δ CD8 CD33 CD80 CD28δ CD3ζ CD33 CD80 CD28δ CD3δ CD33 CD80 CD28δCD3γ CD33 CD80 CD28δ CD3ε CD33 CD80 CD28δ FcγRI-γ CD33 CD80 CD28δFcγRIII-γ CD33 CD80 CD28δ FcεRIβ CD33 CD80 CD28δ FcεRIγ CD33 CD80 CD28δDAP10 CD33 CD80 CD28δ DAP12 CD33 CD80 CD28δ CD32 CD33 CD80 CD28δ CD79aCD33 CD80 CD28δ CD79b CD33 CD80 CD80 CD8 CD33 CD80 CD80 CD3ζ CD33 CD80CD80 CD3δ CD33 CD80 CD80 CD3γ CD33 CD80 CD80 CD3ε CD33 CD80 CD80 FcγRI-γCD33 CD80 CD80 FcγRIII-γ CD33 CD80 CD80 FcεRIβ CD33 CD80 CD80 FcεRIγCD33 CD80 CD80 DAP10 CD33 CD80 CD80 DAP12 CD33 CD80 CD80 CD32 CD33 CD80CD80 CD79a CD33 CD80 CD80 CD79b CD33 CD80 CD86 CD8 CD33 CD80 CD86 CD3ζCD33 CD80 CD86 CD3δ CD33 CD80 CD86 CD3γ CD33 CD80 CD86 CD3ε CD33 CD80CD86 FcγRI-γ CD33 CD80 CD86 FcγRIII-γ CD33 CD80 CD86 FcεRIβ CD33 CD80CD86 FcεRIγ CD33 CD80 CD86 DAP10 CD33 CD80 CD86 DAP12 CD33 CD80 CD86CD32 CD33 CD80 CD86 CD79a CD33 CD80 CD86 CD79b CD33 CD80 OX40 CD8 CD33CD80 OX40 CD3ζ CD33 CD80 OX40 CD3δ CD33 CD80 OX40 CD3γ CD33 CD80 OX40CD3ε CD33 CD80 OX40 FcγRI-γ CD33 CD80 OX40 FcγRIII-γ CD33 CD80 OX40FcεRIβ CD33 CD80 OX40 FcεRIγ CD33 CD80 OX40 DAP10 CD33 CD80 OX40 DAP12CD33 CD80 OX40 CD32 CD33 CD80 OX40 CD79a CD33 CD80 OX40 CD79b CD33 CD80DAP10 CD8 CD33 CD80 DAP10 CD3ζ CD33 CD80 DAP10 CD3δ CD33 CD80 DAP10 CD3γCD33 CD80 DAP10 CD3ε CD33 CD80 DAP10 FcγRI-γ CD33 CD80 DAP10 FcγRIII-γCD33 CD80 DAP10 FcεRIβ CD33 CD80 DAP10 FcεRIγ CD33 CD80 DAP10 DAP10 CD33CD80 DAP10 DAP12 CD33 CD80 DAP10 CD32 CD33 CD80 DAP10 CD79a CD33 CD80DAP10 CD79b CD33 CD80 DAP12 CD8 CD33 CD80 DAP12 CD3ζ CD33 CD80 DAP12CD3δ CD33 CD80 DAP12 CD3γ CD33 CD80 DAP12 CD3ε CD33 CD80 DAP12 FcγRI-γCD33 CD80 DAP12 FcγRIII-γ CD33 CD80 DAP12 FcεRIβ CD33 CD80 DAP12 FcεRIγCD33 CD80 DAP12 DAP10 CD33 CD80 DAP12 DAP12 CD33 CD80 DAP12 CD32 CD33CD80 DAP12 CD79a CD33 CD80 DAP12 CD79b CD33 CD80 MyD88 CD8 CD33 CD80MyD88 CD3ζ CD33 CD80 MyD88 CD3δ CD33 CD80 MyD88 CD3γ CD33 CD80 MyD88CD3ε CD33 CD80 MyD88 FcγRI-γ CD33 CD80 MyD88 FcγRIII-γ CD33 CD80 MyD88FcεRIβ CD33 CD80 MyD88 FcεRIγ CD33 CD80 MyD88 DAP10 CD33 CD80 MyD88DAP12 CD33 CD80 MyD88 CD32 CD33 CD80 MyD88 CD79a CD33 CD80 MyD88 CD79bCD33 CD80 CD7 CD8 CD33 CD80 CD7 CD3ζ CD33 CD80 CD7 CD3δ CD33 CD80 CD7CD3γ CD33 CD80 CD7 CD3ε CD33 CD80 CD7 FcγRI-γ CD33 CD80 CD7 FcγRIII-γCD33 CD80 CD7 FcεRIβ CD33 CD80 CD7 FcεRIγ CD33 CD80 CD7 DAP10 CD33 CD80CD7 DAP12 CD33 CD80 CD7 CD32 CD33 CD80 CD7 CD79a CD33 CD80 CD7 CD79bCD33 CD80 BTNL3 CD8 CD33 CD80 BTNL3 CD3ζ CD33 CD80 BTNL3 CD3δ CD33 CD80BTNL3 CD3γ CD33 CD80 BTNL3 CD3ε CD33 CD80 BTNL3 FcγRI-γ CD33 CD80 BTNL3FcγRIII-γ CD33 CD80 BTNL3 FcεRIβ CD33 CD80 BTNL3 FcεRIγ CD33 CD80 BTNL3DAP10 CD33 CD80 BTNL3 DAP12 CD33 CD80 BTNL3 CD32 CD33 CD80 BTNL3 CD79aCD33 CD80 BTNL3 CD79b CD33 CD80 NKG2D CD8 CD33 CD80 NKG2D CD3ζ CD33 CD80NKG2D CD3δ CD33 CD80 NKG2D CD3γ CD33 CD80 NKG2D CD3ε CD33 CD80 NKG2DFcγRI-γ CD33 CD80 NKG2D FcγRIII-γ CD33 CD80 NKG2D FcεRIβ CD33 CD80 NKG2DFcεRIγ CD33 CD80 NKG2D DAP10 CD33 CD80 NKG2D DAP12 CD33 CD80 NKG2D CD32CD33 CD80 NKG2D CD79a CD33 CD80 NKG2D CD79b CD33 CD86 CD28 CD8 CD33 CD86CD28 CD3ζ CD33 CD86 CD28 CD3δ CD33 CD86 CD28 CD3γ CD33 CD86 CD28 CD3εCD33 CD86 CD28 FcγRI-γ CD33 CD86 CD28 FcγRIII-γ CD33 CD86 CD28 FcεRIβCD33 CD86 CD28 FcεRIγ CD33 CD86 CD28 DAP10 CD33 CD86 CD28 DAP12 CD33CD86 CD28 CD32 CD33 CD86 CD28 CD79a CD33 CD86 CD28 CD79b CD33 CD86 CD8CD8 CD33 CD86 CD8 CD3ζ CD33 CD86 CD8 CD3δ CD33 CD86 CD8 CD3γ CD33 CD86CD8 CD3ε CD33 CD86 CD8 FcγRI-γ CD33 CD86 CD8 FcγRIII-γ CD33 CD86 CD8FcεRIβ CD33 CD86 CD8 FcεRIγ CD33 CD86 CD8 DAP10 CD33 CD86 CD8 DAP12 CD33CD86 CD8 CD32 CD33 CD86 CD8 CD79a CD33 CD86 CD8 CD79b CD33 CD86 CD4 CD8CD33 CD86 CD4 CD3ζ CD33 CD86 CD4 CD3δ CD33 CD86 CD4 CD3γ CD33 CD86 CD4CD3ε CD33 CD86 CD4 FcγRI-γ CD33 CD86 CD4 FcγRIII-γ CD33 CD86 CD4 FcεRIβCD33 CD86 CD4 FcεRIγ CD33 CD86 CD4 DAP10 CD33 CD86 CD4 DAP12 CD33 CD86CD4 CD32 CD33 CD86 CD4 CD79a CD33 CD86 CD4 CD79b CD33 CD86 b2c CD8 CD33CD86 b2c CD3ζ CD33 CD86 b2c CD3δ CD33 CD86 b2c CD3γ CD33 CD86 b2c CD3εCD33 CD86 b2c FcγRI-γ CD33 CD86 b2c FcγRIII-γ CD33 CD86 b2c FcεRIβ CD33CD86 b2c FcεRIγ CD33 CD86 b2c DAP10 CD33 CD86 b2c DAP12 CD33 CD86 b2cCD32 CD33 CD86 b2c CD79a CD33 CD86 b2c CD79b CD33 CD86 CD137/41BB CD8CD33 CD86 CD137/41BB CD3ζ CD33 CD86 CD137/41BB CD3δ CD33 CD86 CD137/41BBCD3γ CD33 CD86 CD137/41BB CD3ε CD33 CD86 CD137/41BB FcγRI-γ CD33 CD86CD137/41BB FcγRIII-γ CD33 CD86 CD137/41BB FcεRIβ CD33 CD86 CD137/41BBFcεRIγ CD33 CD86 CD137/41BB DAP10 CD33 CD86 CD137/41BB DAP12 CD33 CD86CD137/41BB CD32 CD33 CD86 CD137/41BB CD79a CD33 CD86 CD137/41BB CD79bCD33 CD86 ICOS CD8 CD33 CD86 ICOS CD3ζ CD33 CD86 ICOS CD3δ CD33 CD86ICOS CD3γ CD33 CD86 ICOS CD3ε CD33 CD86 ICOS FcγRI-γ CD33 CD86 ICOSFcγRIII-γ CD33 CD86 ICOS FcεRIβ CD33 CD86 ICOS FcεRIγ CD33 CD86 ICOSDAP10 CD33 CD86 ICOS DAP12 CD33 CD86 ICOS CD32 CD33 CD86 ICOS CD79a CD33CD86 ICOS CD79b CD33 CD86 CD27 CD8 CD33 CD86 CD27 CD3ζ CD33 CD86 CD27CD3δ CD33 CD86 CD27 CD3γ CD33 CD86 CD27 CD3ε CD33 CD86 CD27 FcγRI-γ CD33CD86 CD27 FcγRIII-γ CD33 CD86 CD27 FcεRIβ CD33 CD86 CD27 FcεRIγ CD33CD86 CD27 DAP10 CD33 CD86 CD27 DAP12 CD33 CD86 CD27 CD32 CD33 CD86 CD27CD79a CD33 CD86 CD27 CD79b CD33 CD86 CD28δ CD8 CD33 CD86 CD28δ CD3ζ CD33CD86 CD28δ CD3δ CD33 CD86 CD28δ CD3γ CD33 CD86 CD28δ CD3ε CD33 CD86CD28δ FcγRI-γ CD33 CD86 CD28δ FcγRIII-γ CD33 CD86 CD28δ FcεRIβ CD33 CD86CD28δ FcεRIγ CD33 CD86 CD28δ DAP10 CD33 CD86 CD28δ DAP12 CD33 CD86 CD28δCD32 CD33 CD86 CD28δ CD79a CD33 CD86 CD28δ CD79b CD33 CD86 CD80 CD8 CD33CD86 CD80 CD3ζ CD33 CD86 CD80 CD3δ CD33 CD86 CD80 CD3γ CD33 CD86 CD80CD3ε CD33 CD86 CD80 FcγRI-γ CD33 CD86 CD80 FcγRIII-γ CD33 CD86 CD80FcεRIβ CD33 CD86 CD80 FcεRIγ CD33 CD86 CD80 DAP10 CD33 CD86 CD80 DAP12CD33 CD86 CD80 CD32 CD33 CD86 CD80 CD79a CD33 CD86 CD80 CD79b CD33 CD86CD86 CD8 CD33 CD86 CD86 CD3ζ CD33 CD86 CD86 CD3δ CD33 CD86 CD86 CD3γCD33 CD86 CD86 CD3ε CD33 CD86 CD86 FcγRI-γ CD33 CD86 CD86 FcγRIII-γ CD33CD86 CD86 FcεRIβ CD33 CD86 CD86 FcεRIγ CD33 CD86 CD86 DAP10 CD33 CD86CD86 DAP12 CD33 CD86 CD86 CD32 CD33 CD86 CD86 CD79a CD33 CD86 CD86 CD79bCD33 CD86 OX40 CD8 CD33 CD86 OX40 CD3ζ CD33 CD86 OX40 CD3δ CD33 CD86OX40 CD3γ CD33 CD86 OX40 CD3ε CD33 CD86 OX40 FcγRI-γ CD33 CD86 OX40FcγRIII-γ CD33 CD86 OX40 FcεRIβ CD33 CD86 OX40 FcεRIγ CD33 CD86 OX40DAP10 CD33 CD86 OX40 DAP12 CD33 CD86 OX40 CD32 CD33 CD86 OX40 CD79a CD33CD86 OX40 CD79b CD33 CD86 DAP10 CD8 CD33 CD86 DAP10 CD3ζ CD33 CD86 DAP10CD3δ CD33 CD86 DAP10 CD3γ CD33 CD86 DAP10 CD3ε CD33 CD86 DAP10 FcγRI-γCD33 CD86 DAP10 FcγRIII-γ CD33 CD86 DAP10 FcεRIβ CD33 CD86 DAP10 FcεRIγCD33 CD86 DAP10 DAP10 CD33 CD86 DAP10 DAP12 CD33 CD86 DAP10 CD32 CD33CD86 DAP10 CD79a CD33 CD86 DAP10 CD79b CD33 CD86 DAP12 CD8 CD33 CD86DAP12 CD3ζ CD33 CD86 DAP12 CD3δ CD33 CD86 DAP12 CD3γ CD33 CD86 DAP12CD3ε CD33 CD86 DAP12 FcγRI-γ CD33 CD86 DAP12 FcγRIII-γ CD33 CD86 DAP12FcεRIβ CD33 CD86 DAP12 FcεRIγ CD33 CD86 DAP12 DAP10 CD33 CD86 DAP12DAP12 CD33 CD86 DAP12 CD32 CD33 CD86 DAP12 CD79a CD33 CD86 DAP12 CD79bCD33 CD86 MyD88 CD8 CD33 CD86 MyD88 CD3ζ CD33 CD86 MyD88 CD3δ CD33 CD86MyD88 CD3γ CD33 CD86 MyD88 CD3ε CD33 CD86 MyD88 FcγRI-γ CD33 CD86 MyD88FcγRIII-γ CD33 CD86 MyD88 FcεRIβ CD33 CD86 MyD88 FcεRIγ CD33 CD86 MyD88DAP10 CD33 CD86 MyD88 DAP12 CD33 CD86 MyD88 CD32 CD33 CD86 MyD88 CD79aCD33 CD86 MyD88 CD79b CD33 CD86 CD7 CD8 CD33 CD86 CD7 CD3ζ CD33 CD86 CD7CD3δ CD33 CD86 CD7 CD3γ CD33 CD86 CD7 CD3ε CD33 CD86 CD7 FcγRI-γ CD33CD86 CD7 FcγRIII-γ CD33 CD86 CD7 FcεRIβ CD33 CD86 CD7 FcεRIγ CD33 CD86CD7 DAP10 CD33 CD86 CD7 DAP12 CD33 CD86 CD7 CD32 CD33 CD86 CD7 CD79aCD33 CD86 CD7 CD79b CD33 CD86 BTNL3 CD8 CD33 CD86 BTNL3 CD3ζ CD33 CD86BTNL3 CD3δ CD33 CD86 BTNL3 CD3γ CD33 CD86 BTNL3 CD3ε CD33 CD86 BTNL3FcγRI-γ CD33 CD86 BTNL3 FcγRIII-γ CD33 CD86 BTNL3 FcεRIβ CD33 CD86 BTNL3FcεRIγ CD33 CD86 BTNL3 DAP10 CD33 CD86 BTNL3 DAP12 CD33 CD86 BTNL3 CD32CD33 CD86 BTNL3 CD79a CD33 CD86 BTNL3 CD79b CD33 CD86 NKG2D CD8 CD33CD86 NKG2D CD3ζ CD33 CD86 NKG2D CD3δ CD33 CD86 NKG2D CD3γ CD33 CD86NKG2D CD3ε CD33 CD86 NKG2D FcγRI-γ CD33 CD86 NKG2D FcγRIII-γ CD33 CD86NKG2D FcεRIβ CD33 CD86 NKG2D FcεRIγ CD33 CD86 NKG2D DAP10 CD33 CD86NKG2D DAP12 CD33 CD86 NKG2D CD32 CD33 CD86 NKG2D CD79a CD33 CD86 NKG2DCD79b CD33 OX40 CD28 CD8 CD33 OX40 CD28 CD3ζ CD33 OX40 CD28 CD3δ CD33OX40 CD28 CD3γ CD33 OX40 CD28 CD3ε CD33 OX40 CD28 FcγRI-γ CD33 OX40 CD28FcγRIII-γ CD33 OX40 CD28 FcεRIβ CD33 OX40 CD28 FcεRIγ CD33 OX40 CD28DAP10 CD33 OX40 CD28 DAP12 CD33 OX40 CD28 CD32 CD33 OX40 CD28 CD79a CD33OX40 CD28 CD79b CD33 OX40 CD8 CD8 CD33 OX40 CD8 CD3ζ CD33 OX40 CD8 CD3δCD33 OX40 CD8 CD3γ CD33 OX40 CD8 CD3ε CD33 OX40 CD8 FcγRI-γ CD33 OX40CD8 FcγRIII-γ CD33 OX40 CD8 FcεRIβ CD33 OX40 CD8 FcεRIγ CD33 OX40 CD8DAP10 CD33 OX40 CD8 DAP12 CD33 OX40 CD8 CD32 CD33 OX40 CD8 CD79a CD33OX40 CD8 CD79b CD33 OX40 CD4 CD8 CD33 OX40 CD4 CD3ζ CD33 OX40 CD4 CD3δCD33 OX40 CD4 CD3γ CD33 OX40 CD4 CD3ε CD33 OX40 CD4 FcγRI-γ CD33 OX40CD4 FcγRIII-γ CD33 OX40 CD4 FcεRIβ CD33 OX40 CD4 FcεRIγ CD33 OX40 CD4DAP10 CD33 OX40 CD4 DAP12 CD33 OX40 CD4 CD32 CD33 OX40 CD4 CD79a CD33OX40 CD4 CD79b CD33 OX40 b2c CD8 CD33 OX40 b2c CD3ζ CD33 OX40 b2c CD3δCD33 OX40 b2c CD3γ CD33 OX40 b2c CD3ε CD33 OX40 b2c FcγRI-γ CD33 OX40b2c FcγRIII-γ CD33 OX40 b2c FcεRIβ CD33 OX40 b2c FcεRIγ CD33 OX40 b2cDAP10 CD33 OX40 b2c DAP12 CD33 OX40 b2c CD32 CD33 OX40 b2c CD79a CD33OX40 b2c CD79b CD33 OX40 CD137/41BB CD8 CD33 OX40 CD137/41BB CD3ζ CD33OX40 CD137/41BB CD3δ CD33 OX40 CD137/41BB CD3γ CD33 OX40 CD137/41BB CD3εCD33 OX40 CD137/41BB FcγRI-γ CD33 OX40 CD137/41BB FcγRIII-γ CD33 OX40CD137/41BB FcεRIβ CD33 OX40 CD137/41BB FcεRIγ CD33 OX40 CD137/41BB DAP10CD33 OX40 CD137/41BB DAP12 CD33 OX40 CD137/41BB CD32 CD33 OX40CD137/41BB CD79a CD33 OX40 CD137/41BB CD79b CD33 OX40 ICOS CD8 CD33 OX40ICOS CD3ζ CD33 OX40 ICOS CD3δ CD33 OX40 ICOS CD3γ CD33 OX40 ICOS CD3εCD33 OX40 ICOS FcγRI-γ CD33 OX40 ICOS FcγRIII-γ CD33 OX40 ICOS FcεRIβCD33 OX40 ICOS FcεRIγ CD33 OX40 ICOS DAP10 CD33 OX40 ICOS DAP12 CD33OX40 ICOS CD32 CD33 OX40 ICOS CD79a CD33 OX40 ICOS CD79b CD33 OX40 CD27CD8 CD33 OX40 CD27 CD3ζ CD33 OX40 CD27 CD3δ CD33 OX40 CD27 CD3γ CD33OX40 CD27 CD3ε CD33 OX40 CD27 FcγRI-γ CD33 OX40 CD27 FcγRIII-γ CD33 OX40CD27 FcεRIβ CD33 OX40 CD27 FcεRIγ CD33 OX40 CD27 DAP10 CD33 OX40 CD27DAP12 CD33 OX40 CD27 CD32 CD33 OX40 CD27 CD79a CD33 OX40 CD27 CD79b CD33OX40 CD28δ CD8 CD33 OX40 CD28δ CD3ζ CD33 OX40 CD28δ CD3δ CD33 OX40 CD28δCD3γ CD33 OX40 CD28δ CD3ε CD33 OX40 CD28δ FcγRI-γ CD33 OX40 CD28δ CD28δCD33 OX40 CD28δ FcεRIβ CD33 OX40 CD28δ FcεRIγ CD33 OX40 CD28δ DAP10 CD33OX40 CD28δ DAP12 CD33 OX40 CD28δ CD32 CD33 OX40 CD28δ CD79a CD33 OX40CD28δ CD79b CD33 OX40 CD80 CD8 CD33 OX40 CD80 CD3ζ CD33 OX40 CD80 CD3δCD33 OX40 CD80 CD3γ CD33 OX40 CD80 CD3ε CD33 OX40 CD80 FcγRI-γ CD33 OX40CD80 FcγRIII-γ CD33 OX40 CD80 FcεRIβ CD33 OX40 CD80 FcεRIγ CD33 OX40CD80 DAP10 CD33 OX40 CD80 DAP12 CD33 OX40 CD80 CD32 CD33 OX40 CD80 CD79aCD33 OX40 CD80 CD79b CD33 OX40 CD86 CD8 CD33 OX40 CD86 CD3ζ CD33 OX40CD86 CD3δ CD33 OX40 CD86 CD3γ CD33 OX40 CD86 CD3ε CD33 OX40 CD86 FcγRI-γCD33 OX40 CD86 FcγRIII-γ CD33 OX40 CD86 FcεRIβ CD33 OX40 CD86 FcεRIγCD33 OX40 CD86 DAP10 CD33 OX40 CD86 DAP12 CD33 OX40 CD86 CD32 CD33 OX40CD86 CD79a CD33 OX40 CD86 CD79b CD33 OX40 OX40 CD8 CD33 OX40 OX40 CD3ζCD33 OX40 OX40 CD3δ CD33 OX40 OX40 CD3γ CD33 OX40 OX40 CD3ε CD33 OX40OX40 FcγRI-γ CD33 OX40 OX40 FcγRIII-γ CD33 OX40 OX40 FcεRIβ CD33 OX40OX40 FcεRIγ CD33 OX40 OX40 DAP10 CD33 OX40 OX40 DAP12 CD33 OX40 OX40CD32 CD33 OX40 OX40 CD79a CD33 OX40 OX40 CD79b CD33 OX40 DAP10 CD8 CD33OX40 DAP10 CD3ζ CD33 OX40 DAP10 CD3δ CD33 OX40 DAP10 CD3γ CD33 OX40DAP10 CD3ε CD33 OX40 DAP10 FcγRI-γ CD33 OX40 DAP10 FcγRIII-γ CD33 OX40DAP10 FcεRIβ CD33 OX40 DAP10 FcεRIγ CD33 OX40 DAP10 DAP10 CD33 OX40DAP10 DAP12 CD33 OX40 DAP10 CD32 CD33 OX40 DAP10 CD79a CD33 OX40 DAP10CD79b CD33 OX40 DAP12 CD8 CD33 OX40 DAP12 CD3ζ CD33 OX40 DAP12 CD3δ CD33OX40 DAP12 CD3γ CD33 OX40 DAP12 CD3ε CD33 OX40 DAP12 FcγRI-γ CD33 OX40DAP12 FcγRIII-γ CD33 OX40 DAP12 FcεRIβ CD33 OX40 DAP12 FcεRIγ CD33 OX40DAP12 DAP10 CD33 OX40 DAP12 DAP12 CD33 OX40 DAP12 CD32 CD33 OX40 DAP12CD79a CD33 OX40 DAP12 CD79b CD33 OX40 MyD88 CD8 CD33 OX40 MyD88 CD3ζCD33 OX40 MyD88 CD3δ CD33 OX40 MyD88 CD3γ CD33 OX40 MyD88 CD3ε CD33 OX40MyD88 FcγRI-γ CD33 OX40 MyD88 FcγRIII-γ CD33 OX40 MyD88 FcεRIβ CD33 OX40MyD88 FcεRIγ CD33 OX40 MyD88 DAP10 CD33 OX40 MyD88 DAP12 CD33 OX40 MyD88CD32 CD33 OX40 MyD88 CD79a CD33 OX40 MyD88 CD79b CD33 OX40 CD7 CD8 CD33OX40 CD7 CD3ζ CD33 OX40 CD7 CD3δ CD33 OX40 CD7 CD3γ CD33 OX40 CD7 CD3εCD33 OX40 CD7 FcγRI-γ CD33 OX40 CD7 FcγRIII-γ CD33 OX40 CD7 FcεRIβ CD33OX40 CD7 FcεRIγ CD33 OX40 CD7 DAP10 CD33 OX40 CD7 DAP12 CD33 OX40 CD7CD32 CD33 OX40 CD7 CD79a CD33 OX40 CD7 CD79b CD33 OX40 BTNL3 CD8 CD33OX40 BTNL3 CD3ζ CD33 OX40 BTNL3 CD3δ CD33 OX40 BTNL3 CD3γ CD33 OX40BTNL3 CD3ε CD33 OX40 BTNL3 FcγRI-γ CD33 OX40 BTNL3 FcγRIII-γ CD33 OX40BTNL3 FcεRIβ CD33 OX40 BTNL3 FcεRIγ CD33 OX40 BTNL3 DAP10 CD33 OX40BTNL3 DAP12 CD33 OX40 BTNL3 CD32 CD33 OX40 BTNL3 CD79a CD33 OX40 BTNL3CD79b CD33 OX40 NKG2D CD8 CD33 OX40 NKG2D CD3ζ CD33 OX40 NKG2D CD3δ CD33OX40 NKG2D CD3γ CD33 OX40 NKG2D CD3ε CD33 OX40 NKG2D FcγRI-γ CD33 OX40NKG2D FcγRIII-γ CD33 OX40 NKG2D FcεRIβ CD33 OX40 NKG2D FcεRIγ CD33 OX40NKG2D DAP10 CD33 OX40 NKG2D DAP12 CD33 OX40 NKG2D CD32 CD33 OX40 NKG2DCD79a CD33 OX40 NKG2D CD79b CD33 DAP10 CD28 CD8 CD33 DAP10 CD28 CD3ζCD33 DAP10 CD28 CD3δ CD33 DAP10 CD28 CD3γ CD33 DAP10 CD28 CD3ε CD33DAP10 CD28 FcγRI-γ CD33 DAP10 CD28 FcγRIII-γ CD33 DAP10 CD28 FcεRIβ CD33DAP10 CD28 FcεRIγ CD33 DAP10 CD28 DAP10 CD33 DAP10 CD28 DAP12 CD33 DAP10CD28 CD32 CD33 DAP10 CD28 CD79a CD33 DAP10 CD28 CD79b CD33 DAP10 CD8 CD8CD33 DAP10 CD8 CD3ζ CD33 DAP10 CD8 CD3δ CD33 DAP10 CD8 CD3γ CD33 DAP10CD8 CD3ε CD33 DAP10 CD8 FcγRI-γ CD33 DAP10 CD8 FcγRIII-γ CD33 DAP10 CD8FcεRIβ CD33 DAP10 CD8 FcεRIγ CD33 DAP10 CD8 DAP10 CD33 DAP10 CD8 DAP12CD33 DAP10 CD8 CD32 CD33 DAP10 CD8 CD79a CD33 DAP10 CD8 CD79b CD33 DAP10CD4 CD8 CD33 DAP10 CD4 CD3ζ CD33 DAP10 CD4 CD3δ CD33 DAP10 CD4 CD3γ CD33DAP10 CD4 CD3ε CD33 DAP10 CD4 FcγRI-γ CD33 DAP10 CD4 FcγRIII-γ CD33DAP10 CD4 FcεRIβ CD33 DAP10 CD4 FcεRIγ CD33 DAP10 CD4 DAP10 CD33 DAP10CD4 DAP12 CD33 DAP10 CD4 CD32 CD33 DAP10 CD4 CD79a CD33 DAP10 CD4 CD79bCD33 DAP10 b2c CD8 CD33 DAP10 b2c CD3ζ CD33 DAP10 b2c CD3δ CD33 DAP10b2c CD3γ CD33 DAP10 b2c CD3ε CD33 DAP10 b2c FcγRI-γ CD33 DAP10 b2cFcγRIII-γ CD33 DAP10 b2c FcεRIβ CD33 DAP10 b2c FcεRIγ CD33 DAP10 b2cDAP10 CD33 DAP10 b2c DAP12 CD33 DAP10 b2c CD32 CD33 DAP10 b2c CD79a CD33DAP10 b2c CD79b CD33 DAP10 CD137/41BB CD8 CD33 DAP10 CD137/41BB CD3ζCD33 DAP10 CD137/41BB CD3δ CD33 DAP10 CD137/41BB CD3γ CD33 DAP10CD137/41BB CD3ε CD33 DAP10 CD137/41BB FcγRI-γ CD33 DAP10 CD137/41BBFcγRIII-γ CD33 DAP10 CD137/41BB FcεRIβ CD33 DAP10 CD137/41BB FcεRIγ CD33DAP10 CD137/41BB DAP10 CD33 DAP10 CD137/41BB DAP12 CD33 DAP10 CD137/41BBCD32 CD33 DAP10 CD137/41BB CD79a CD33 DAP10 CD137/41BB CD79b CD33 DAP10ICOS CD8 CD33 DAP10 ICOS CD3ζ CD33 DAP10 ICOS CD3δ CD33 DAP10 ICOS CD3γCD33 DAP10 ICOS CD3ε CD33 DAP10 ICOS FcγRI-γ CD33 DAP10 ICOS FcγRIII-γCD33 DAP10 ICOS FcεRIβ CD33 DAP10 ICOS FcεRIγ CD33 DAP10 ICOS DAP10 CD33DAP10 ICOS DAP12 CD33 DAP10 ICOS CD32 CD33 DAP10 ICOS CD79a CD33 DAP10ICOS CD79b CD33 DAP10 CD27 CD8 CD33 DAP10 CD27 CD3ζ CD33 DAP10 CD27 CD3δCD33 DAP10 CD27 CD3γ CD33 DAP10 CD27 CD3ε CD33 DAP10 CD27 FcγRI-γ CD33DAP10 CD27 FcγRIII-γ CD33 DAP10 CD27 FcεRIβ CD33 DAP10 CD27 FcεRIγ CD33DAP10 CD27 DAP10 CD33 DAP10 CD27 DAP12 CD33 DAP10 CD27 CD32 CD33 DAP10CD27 CD79a CD33 DAP10 CD27 CD79b CD33 DAP10 CD28δ CD8 CD33 DAP10 CD28δCD3ζ CD33 DAP10 CD28δ CD3δ CD33 DAP10 CD28δ CD3γ CD33 DAP10 CD28δ CD3εCD33 DAP10 CD28δ FcγRI-γ CD33 DAP10 CD28δ FcγRIII-γ CD33 DAP10 CD28δFcεRIβ CD33 DAP10 CD28δ FcεRIγ CD33 DAP10 CD28δ DAP10 CD33 DAP10 CD28δDAP12 CD33 DAP10 CD28δ CD32 CD33 DAP10 CD28δ CD79a CD33 DAP10 CD28δCD79b CD33 DAP10 CD80 CD8 CD33 DAP10 CD80 CD3ζ CD33 DAP10 CD80 CD3δ CD33DAP10 CD80 CD3γ CD33 DAP10 CD80 CD3ε CD33 DAP10 CD80 FcγRI-γ CD33 DAP10CD80 FcγRIII-γ CD33 DAP10 CD80 FcεRIβ CD33 DAP10 CD80 FcεRIγ CD33 DAP10CD80 DAP10 CD33 DAP10 CD80 DAP12 CD33 DAP10 CD80 CD32 CD33 DAP10 CD80CD79a CD33 DAP10 CD80 CD79b CD33 DAP10 CD86 CD8 CD33 DAP10 CD86 CD3ζCD33 DAP10 CD86 CD3δ CD33 DAP10 CD86 CD3γ CD33 DAP10 CD86 CD3ε CD33DAP10 CD86 FcγRI-γ CD33 DAP10 CD86 FcγRIII-γ CD33 DAP10 CD86 FcεRIβ CD33DAP10 CD86 FcεRIγ CD33 DAP10 CD86 DAP10 CD33 DAP10 CD86 DAP12 CD33 DAP10CD86 CD32 CD33 DAP10 CD86 CD79a CD33 DAP10 CD86 CD79b CD33 DAP10 OX40CD8 CD33 DAP10 OX40 CD3ζ CD33 DAP10 OX40 CD3δ CD33 DAP10 OX40 CD3γ CD33DAP10 OX40 CD3ε CD33 DAP10 OX40 FcγRI-γ CD33 DAP10 OX40 FcγRIII-γ CD33DAP10 OX40 FcεRIβ CD33 DAP10 OX40 FcεRIγ CD33 DAP10 OX40 DAP10 CD33DAP10 OX40 DAP12 CD33 DAP10 OX40 CD32 CD33 DAP10 OX40 CD79a CD33 DAP10OX40 CD79b CD33 DAP10 DAP10 CD8 CD33 DAP10 DAP10 CD3ζ CD33 DAP10 DAP10CD3δ CD33 DAP10 DAP10 CD3γ CD33 DAP10 DAP10 CD3ε CD33 DAP10 DAP10FcγRI-γ CD33 DAP10 DAP10 FcγRIII-γ CD33 DAP10 DAP10 FcεRIβ CD33 DAP10DAP10 FcεRIγ CD33 DAP10 DAP10 DAP10 CD33 DAP10 DAP10 DAP12 CD33 DAP10DAP10 CD32 CD33 DAP10 DAP10 CD79a CD33 DAP10 DAP10 CD79b CD33 DAP10DAP12 CD8 CD33 DAP10 DAP12 CD3ζ CD33 DAP10 DAP12 CD3δ CD33 DAP10 DAP12CD3γ CD33 DAP10 DAP12 CD3ε CD33 DAP10 DAP12 FcγRI-γ CD33 DAP10 DAP12FcγRIII-γ CD33 DAP10 DAP12 FcεRIβ CD33 DAP10 DAP12 FcεRIγ CD33 DAP10DAP12 DAP10 CD33 DAP10 DAP12 DAP12 CD33 DAP10 DAP12 CD32 CD33 DAP10DAP12 CD79a CD33 DAP10 DAP12 CD79b CD33 DAP10 MyD88 CD8 CD33 DAP10 MyD88CD3ζ CD33 DAP10 MyD88 CD3δ CD33 DAP10 MyD88 CD3γ CD33 DAP10 MyD88 CD3εCD33 DAP10 MyD88 FcγRI-γ CD33 DAP10 MyD88 FcγRIII-γ CD33 DAP10 MyD88FcεRIβ CD33 DAP10 MyD88 FcεRIγ CD33 DAP10 MyD88 DAP10 CD33 DAP10 MyD88DAP12 CD33 DAP10 MyD88 CD32 CD33 DAP10 MyD88 CD79a CD33 DAP10 MyD88CD79b CD33 DAP10 CD7 CD8 CD33 DAP10 CD7 CD3ζ CD33 DAP10 CD7 CD3δ CD33DAP10 CD7 CD3γ CD33 DAP10 CD7 CD3ε CD33 DAP10 CD7 FcγRI-γ CD33 DAP10 CD7FcγRIII-γ CD33 DAP10 CD7 FcεRIβ CD33 DAP10 CD7 FcεRIγ CD33 DAP10 CD7DAP10 CD33 DAP10 CD7 DAP12 CD33 DAP10 CD7 CD32 CD33 DAP10 CD7 CD79a CD33DAP10 CD7 CD79b CD33 DAP10 BTNL3 CD8 CD33 DAP10 BTNL3 CD3ζ CD33 DAP10BTNL3 CD3δ CD33 DAP10 BTNL3 CD3γ CD33 DAP10 BTNL3 CD3ε CD33 DAP10 BTNL3FcγRI-γ CD33 DAP10 BTNL3 FcγRIII-γ CD33 DAP10 BTNL3 FcεRIβ CD33 DAP10BTNL3 FcεRIγ CD33 DAP10 BTNL3 DAP10 CD33 DAP10 BTNL3 DAP12 CD33 DAP10BTNL3 CD32 CD33 DAP10 BTNL3 CD79a CD33 DAP10 BTNL3 CD79b CD33 DAP10NKG2D CD8 CD33 DAP10 NKG2D CD3ζ CD33 DAP10 NKG2D CD3δ CD33 DAP10 NKG2DCD3γ CD33 DAP10 NKG2D CD3ε CD33 DAP10 NKG2D FcγRI-γ CD33 DAP10 NKG2DFcγRIII-γ CD33 DAP10 NKG2D FcεRIβ CD33 DAP10 NKG2D FcεRIγ CD33 DAP10NKG2D DAP10 CD33 DAP10 NKG2D DAP12 CD33 DAP10 NKG2D CD32 CD33 DAP10NKG2D CD79a CD33 DAP10 NKG2D CD79b CD33 DAP12 CD28 CD8 CD33 DAP12 CD28CD3ζ CD33 DAP12 CD28 CD3δ CD33 DAP12 CD28 CD3γ CD33 DAP12 CD28 CD3ε CD33DAP12 CD28 FcγRI-γ CD33 DAP12 CD28 FcγRIII-γ CD33 DAP12 CD28 FcεRIβ CD33DAP12 CD28 FcεRIγ CD33 DAP12 CD28 DAP10 CD33 DAP12 CD28 DAP12 CD33 DAP12CD28 CD32 CD33 DAP12 CD28 CD79a CD33 DAP12 CD28 CD79b CD33 DAP12 CD8 CD8CD33 DAP12 CD8 CD3ζ CD33 DAP12 CD8 CD3δ CD33 DAP12 CD8 CD3γ CD33 DAP12CD8 CD3ε CD33 DAP12 CD8 FcγRI-γ CD33 DAP12 CD8 FcγRIII-γ CD33 DAP12 CD8FcεRIβ CD33 DAP12 CD8 FcεRIγ CD33 DAP12 CD8 DAP10 CD33 DAP12 CD8 DAP12CD33 DAP12 CD8 CD32 CD33 DAP12 CD8 CD79a CD33 DAP12 CD8 CD79b CD33 DAP12CD4 CD8 CD33 DAP12 CD4 CD3ζ CD33 DAP12 CD4 CD3δ CD33 DAP12 CD4 CD3γ CD33DAP12 CD4 CD3ε CD33 DAP12 CD4 FcγRI-γ CD33 DAP12 CD4 FcγRIII-γ CD33DAP12 CD4 FcεRIβ CD33 DAP12 CD4 FcεRIγ CD33 DAP12 CD4 DAP10 CD33 DAP12CD4 DAP12 CD33 DAP12 CD4 CD32 CD33 DAP12 CD4 CD79a CD33 DAP12 CD4 CD79bCD33 DAP12 b2c CD8 CD33 DAP12 b2c CD3ζ CD33 DAP12 b2c CD3δ CD33 DAP12b2c CD3γ CD33 DAP12 b2c CD3ε CD33 DAP12 b2c FcγRI-γ CD33 DAP12 b2cFcγRIII-γ CD33 DAP12 b2c FcεRIβ CD33 DAP12 b2c FcεRIγ CD33 DAP12 b2cDAP10 CD33 DAP12 b2c DAP12 CD33 DAP12 b2c CD32 CD33 DAP12 b2c CD79a CD33DAP12 b2c CD79b CD33 DAP12 CD137/41BB CD8 CD33 DAP12 CD137/41BB CD3ζCD33 DAP12 CD137/41BB CD3δ CD33 DAP12 CD137/41BB CD3γ CD33 DAP12CD137/41BB CD3ε CD33 DAP12 CD137/41BB FcγRI-γ CD33 DAP12 CD137/41BBFcγRIII-γ CD33 DAP12 CD137/41BB FcεRIβ CD33 DAP12 CD137/41BB FcεRIγ CD33DAP12 CD137/41BB DAP10 CD33 DAP12 CD137/41BB DAP12 CD33 DAP12 CD137/41BBCD32 CD33 DAP12 CD137/41BB CD79a CD33 DAP12 CD137/41BB CD79b CD33 DAP12ICOS CD8 CD33 DAP12 ICOS CD3ζ CD33 DAP12 ICOS CD3δ CD33 DAP12 ICOS CD3γCD33 DAP12 ICOS CD3ε CD33 DAP12 ICOS FcγRI-γ CD33 DAP12 ICOS FcγRIII-γCD33 DAP12 ICOS FcεRIβ CD33 DAP12 ICOS FcεRIγ CD33 DAP12 ICOS DAP10 CD33DAP12 ICOS DAP12 CD33 DAP12 ICOS CD32 CD33 DAP12 ICOS CD79a CD33 DAP12ICOS CD79b CD33 DAP12 CD27 CD8 CD33 DAP12 CD27 CD3ζ CD33 DAP12 CD27 CD3δCD33 DAP12 CD27 CD3γ CD33 DAP12 CD27 CD3ε CD33 DAP12 CD27 FcγRI-γ CD33DAP12 CD27 FcγRIII-γ CD33 DAP12 CD27 FcεRIβ CD33 DAP12 CD27 FcεRIγ CD33DAP12 CD27 DAP10 CD33 DAP12 CD27 DAP12 CD33 DAP12 CD27 CD32 CD33 DAP12CD27 CD79a CD33 DAP12 CD27 CD79b CD33 DAP12 CD28δ CD8 CD33 DAP12 CD28δCD3ζ CD33 DAP12 CD28δ CD3δ CD33 DAP12 CD28δ CD3γ CD33 DAP12 CD28δ CD3εCD33 DAP12 CD28δ FcγRI-γ CD33 DAP12 CD28δ FcγRIII-γ CD33 DAP12 CD28δFcεRIβ CD33 DAP12 CD28δ FcεRIγ CD33 DAP12 CD28δ DAP10 CD33 DAP12 CD28δDAP12 CD33 DAP12 CD28δ CD32 CD33 DAP12 CD28δ CD79a CD33 DAP12 CD28δCD79b CD33 DAP12 CD80 CD8 CD33 DAP12 CD80 CD3ζ CD33 DAP12 CD80 CD3δ CD33DAP12 CD80 CD3γ CD33 DAP12 CD80 CD3ε CD33 DAP12 CD80 FcγRI-γ CD33 DAP12CD80 FcγRIII-γ CD33 DAP12 CD80 FcεRIβ CD33 DAP12 CD80 FcεRIγ CD33 DAP12CD80 DAP10 CD33 DAP12 CD80 DAP12 CD33 DAP12 CD80 CD32 CD33 DAP12 CD80CD79a CD33 DAP12 CD80 CD79b CD33 DAP12 CD86 CD8 CD33 DAP12 CD86 CD3ζCD33 DAP12 CD86 CD3δ CD33 DAP12 CD86 CD3γ CD33 DAP12 CD86 CD3ε CD33DAP12 CD86 FcγRI-γ CD33 DAP12 CD86 FcγRIII-γ CD33 DAP12 CD86 FcεRIβ CD33DAP12 CD86 FcεRIγ CD33 DAP12 CD86 DAP10 CD33 DAP12 CD86 DAP12 CD33 DAP12CD86 CD32 CD33 DAP12 CD86 CD79a CD33 DAP12 CD86 CD79b CD33 DAP12 OX40CD8 CD33 DAP12 OX40 CD3ζ CD33 DAP12 OX40 CD3δ CD33 DAP12 OX40 CD3γ CD33DAP12 OX40 CD3ε CD33 DAP12 OX40 FcγRI-γ CD33 DAP12 OX40 FcγRIII-γ CD33DAP12 OX40 FcεRIβ CD33 DAP12 OX40 FcεRIγ CD33 DAP12 OX40 DAP10 CD33DAP12 OX40 DAP12 CD33 DAP12 OX40 CD32 CD33 DAP12 OX40 CD79a CD33 DAP12OX40 CD79b CD33 DAP12 DAP10 CD8 CD33 DAP12 DAP10 CD3ζ CD33 DAP12 DAP10CD3δ CD33 DAP12 DAP10 CD3γ CD33 DAP12 DAP10 CD3ε CD33 DAP12 DAP10FcγRI-γ CD33 DAP12 DAP10 FcγRIII-γ CD33 DAP12 DAP10 FcεRIβ CD33 DAP12DAP10 FcεRIγ CD33 DAP12 DAP10 DAP10 CD33 DAP12 DAP10 DAP12 CD33 DAP12DAP10 CD32 CD33 DAP12 DAP10 CD79a CD33 DAP12 DAP10 CD79b CD33 DAP12DAP12 CD8 CD33 DAP12 DAP12 CD3ζ CD33 DAP12 DAP12 CD3δ CD33 DAP12 DAP12CD3γ CD33 DAP12 DAP12 CD3ε CD33 DAP12 DAP12 FcγRI-γ CD33 DAP12 DAP12FcγRIII-γ CD33 DAP12 DAP12 FcεRIβ CD33 DAP12 DAP12 FcεRIγ CD33 DAP12DAP12 DAP10 CD33 DAP12 DAP12 DAP12 CD33 DAP12 DAP12 CD32 CD33 DAP12DAP12 CD79a CD33 DAP12 DAP12 CD79b CD33 DAP12 MyD88 CD8 CD33 DAP12 MyD88CD3ζ CD33 DAP12 MyD88 CD3δ CD33 DAP12 MyD88 CD3γ CD33 DAP12 MyD88 CD3εCD33 DAP12 MyD88 FcγRI-γ CD33 DAP12 MyD88 FcγRIII-γ CD33 DAP12 MyD88FcεRIβ CD33 DAP12 MyD88 FcεRIγ CD33 DAP12 MyD88 DAP10 CD33 DAP12 MyD88DAP12 CD33 DAP12 MyD88 CD32 CD33 DAP12 MyD88 CD79a CD33 DAP12 MyD88CD79b CD33 DAP12 CD7 CD8 CD33 DAP12 CD7 CD3ζ CD33 DAP12 CD7 CD3δ CD33DAP12 CD7 CD3γ CD33 DAP12 CD7 CD3ε CD33 DAP12 CD7 FcγRI-γ CD33 DAP12 CD7FcγRIII-γ CD33 DAP12 CD7 FcεRIβ CD33 DAP12 CD7 FcεRIγ CD33 DAP12 CD7DAP10 CD33 DAP12 CD7 DAP12 CD33 DAP12 CD7 CD32 CD33 DAP12 CD7 CD79a CD33DAP12 CD7 CD79b CD33 DAP12 BTNL3 CD8 CD33 DAP12 BTNL3 CD3ζ CD33 DAP12BTNL3 CD3δ CD33 DAP12 BTNL3 CD3γ CD33 DAP12 BTNL3 CD3ε CD33 DAP12 BTNL3FcγRI-γ CD33 DAP12 BTNL3 FcγRIII-γ CD33 DAP12 BTNL3 FcεRIβ CD33 DAP12BTNL3 FcεRIγ CD33 DAP12 BTNL3 DAP10 CD33 DAP12 BTNL3 DAP12 CD33 DAP12BTNL3 CD32 CD33 DAP12 BTNL3 CD79a CD33 DAP12 BTNL3 CD79b CD33 DAP12NKG2D CD8 CD33 DAP12 NKG2D CD3ζ CD33 DAP12 NKG2D CD3δ CD33 DAP12 NKG2DCD3γ CD33 DAP12 NKG2D CD3ε CD33 DAP12 NKG2D FcγRI-γ CD33 DAP12 NKG2DFcγRIII-γ CD33 DAP12 NKG2D FcεRIβ CD33 DAP12 NKG2D FcεRIγ CD33 DAP12NKG2D DAP10 CD33 DAP12 NKG2D DAP12 CD33 DAP12 NKG2D CD32 CD33 DAP12NKG2D CD79a CD33 DAP12 NKG2D CD79b CD33 MyD88 CD28 CD8 CD33 MyD88 CD28CD3ζ CD33 MyD88 CD28 CD3δ CD33 MyD88 CD28 CD3γ CD33 MyD88 CD28 CD3ε CD33MyD88 CD28 FcγRI-γ CD33 MyD88 CD28 FcγRIII-γ CD33 MyD88 CD28 FcεRIβ CD33MyD88 CD28 FcεRIγ CD33 MyD88 CD28 DAP10 CD33 MyD88 CD28 DAP12 CD33 MyD88CD28 CD32 CD33 MyD88 CD28 CD79a CD33 MyD88 CD28 CD79b CD33 MyD88 CD8 CD8CD33 MyD88 CD8 CD3ζ CD33 MyD88 CD8 CD3δ CD33 MyD88 CD8 CD3γ CD33 MyD88CD8 CD3ε CD33 MyD88 CD8 FcγRI-γ CD33 MyD88 CD8 FcγRIII-γ CD33 MyD88 CD8FcεRIβ CD33 MyD88 CD8 FcεRIγ CD33 MyD88 CD8 DAP10 CD33 MyD88 CD8 DAP12CD33 MyD88 CD8 CD32 CD33 MyD88 CD8 CD79a CD33 MyD88 CD8 CD79b CD33 MyD88CD4 CD8 CD33 MyD88 CD4 CD3ζ CD33 MyD88 CD4 CD3δ CD33 MyD88 CD4 CD3γ CD33MyD88 CD4 CD3ε CD33 MyD88 CD4 FcγRI-γ CD33 MyD88 CD4 FcγRIII-γ CD33MyD88 CD4 FcεRIβ CD33 MyD88 CD4 FcεRIγ CD33 MyD88 CD4 DAP10 CD33 MyD88CD4 DAP12 CD33 MyD88 CD4 CD32 CD33 MyD88 CD4 CD79a CD33 MyD88 CD4 CD79bCD33 MyD88 b2c CD8 CD33 MyD88 b2c CD3ζ CD33 MyD88 b2c CD3δ CD33 MyD88b2c CD3γ CD33 MyD88 b2c CD3ε CD33 MyD88 b2c FcγRI-γ CD33 MyD88 b2cFcγRIII-γ CD33 MyD88 b2c FcεRIβ CD33 MyD88 b2c FcεRIγ CD33 MyD88 b2cDAP10 CD33 MyD88 b2c DAP12 CD33 MyD88 b2c CD32 CD33 MyD88 b2c CD79a CD33MyD88 b2c CD79b CD33 MyD88 CD137/41BB CD8 CD33 MyD88 CD137/41BB CD3ζCD33 MyD88 CD137/41BB CD3δ CD33 MyD88 CD137/41BB CD3γ CD33 MyD88CD137/41BB CD3ε CD33 MyD88 CD137/41BB FcγRI-γ CD33 MyD88 CD137/41BBFcγRIII-γ CD33 MyD88 CD137/41BB FcεRIβ CD33 MyD88 CD137/41BB FcεRIγ CD33MyD88 CD137/41BB DAP10 CD33 MyD88 CD137/41BB DAP12 CD33 MyD88 CD137/41BBCD32 CD33 MyD88 CD137/41BB CD79a CD33 MyD88 CD137/41BB CD79b CD33 MyD88ICOS CD8 CD33 MyD88 ICOS CD3ζ CD33 MyD88 ICOS CD3δ CD33 MyD88 ICOS CD3γCD33 MyD88 ICOS CD3ε CD33 MyD88 ICOS FcγRI-γ CD33 MyD88 ICOS FcγRIII-γCD33 MyD88 ICOS FcεRIβ CD33 MyD88 ICOS FcεRIγ CD33 MyD88 ICOS DAP10 CD33MyD88 ICOS DAP12 CD33 MyD88 ICOS CD32 CD33 MyD88 ICOS CD79a CD33 MyD88ICOS CD79b CD33 MyD88 CD27 CD8 CD33 MyD88 CD27 CD3ζ CD33 MyD88 CD27 CD3δCD33 MyD88 CD27 CD3γ CD33 MyD88 CD27 CD3ε CD33 MyD88 CD27 FcγRI-γ CD33MyD88 CD27 FcγRIII-γ CD33 MyD88 CD27 FcεRIβ CD33 MyD88 CD27 FcεRIγ CD33MyD88 CD27 DAP10 CD33 MyD88 CD27 DAP12 CD33 MyD88 CD27 CD32 CD33 MyD88CD27 CD79a CD33 MyD88 CD27 CD79b CD33 MyD88 CD28δ CD8 CD33 MyD88 CD28δCD3ζ CD33 MyD88 CD28δ CD3δ CD33 MyD88 CD28δ CD3γ CD33 MyD88 CD28δ CD3εCD33 MyD88 CD28δ FcγRI-γ CD33 MyD88 CD28δ FcγRIII-γ CD33 MyD88 CD28δFcεRIβ CD33 MyD88 CD28δ FcεRIγ CD33 MyD88 CD28δ DAP10 CD33 MyD88 CD28δDAP12 CD33 MyD88 CD28δ CD32 CD33 MyD88 CD28δ CD79a CD33 MyD88 CD28δCD79b CD33 MyD88 CD80 CD8 CD33 MyD88 CD80 CD3ζ CD33 MyD88 CD80 CD3δ CD33MyD88 CD80 CD3γ CD33 MyD88 CD80 CD3ε CD33 MyD88 CD80 FcγRI-γ CD33 MyD88CD80 FcγRIII-γ CD33 MyD88 CD80 FcεRIβ CD33 MyD88 CD80 FcεRIγ CD33 MyD88CD80 DAP10 CD33 MyD88 CD80 DAP12 CD33 MyD88 CD80 CD32 CD33 MyD88 CD80CD79a CD33 MyD88 CD80 CD79b CD33 MyD88 CD86 CD8 CD33 MyD88 CD86 CD3ζCD33 MyD88 CD86 CD3δ CD33 MyD88 CD86 CD3γ CD33 MyD88 CD86 CD3ε CD33MyD88 CD86 FcγRI-γ CD33 MyD88 CD86 FcγRIII-γ CD33 MyD88 CD86 FcεRIβ CD33MyD88 CD86 FcεRIγ CD33 MyD88 CD86 DAP10 CD33 MyD88 CD86 DAP12 CD33 MyD88CD86 CD32 CD33 MyD88 CD86 CD79a CD33 MyD88 CD86 CD79b CD33 MyD88 OX40CD8 CD33 MyD88 OX40 CD3ζ CD33 MyD88 OX40 CD3δ CD33 MyD88 OX40 CD3γ CD33MyD88 OX40 CD3ε CD33 MyD88 OX40 FcγRI-γ CD33 MyD88 OX40 FcγRIII-γ CD33MyD88 OX40 FcεRIβ CD33 MyD88 OX40 FcεRIγ CD33 MyD88 OX40 DAP10 CD33MyD88 OX40 DAP12 CD33 MyD88 OX40 CD32 CD33 MyD88 OX40 CD79a CD33 MyD88OX40 CD79b CD33 MyD88 DAP10 CD8 CD33 MyD88 DAP10 CD3ζ CD33 MyD88 DAP10CD3δ CD33 MyD88 DAP10 CD3γ CD33 MyD88 DAP10 CD3ε CD33 MyD88 DAP10FcγRI-γ CD33 MyD88 DAP10 FcγRIII-γ CD33 MyD88 DAP10 FcεRIβ CD33 MyD88DAP10 FcεRIγ CD33 MyD88 DAP10 DAP10 CD33 MyD88 DAP10 DAP12 CD33 MyD88DAP10 CD32 CD33 MyD88 DAP10 CD79a CD33 MyD88 DAP10 CD79b CD33 MyD88DAP12 CD8 CD33 MyD88 DAP12 CD3ζ CD33 MyD88 DAP12 CD3δ CD33 MyD88 DAP12CD3γ CD33 MyD88 DAP12 CD3ε CD33 MyD88 DAP12 FcγRI-γ CD33 MyD88 DAP12FcγRIII-γ CD33 MyD88 DAP12 FcεRIβ CD33 MyD88 DAP12 FcεRIγ CD33 MyD88DAP12 DAP10 CD33 MyD88 DAP12 DAP12 CD33 MyD88 DAP12 CD32 CD33 MyD88DAP12 CD79a CD33 MyD88 DAP12 CD79b CD33 MyD88 MyD88 CD8 CD33 MyD88 MyD88CD3ζ CD33 MyD88 MyD88 CD3δ CD33 MyD88 MyD88 CD3γ CD33 MyD88 MyD88 CD3εCD33 MyD88 MyD88 FcγRI-γ CD33 MyD88 MyD88 FcγRIII-γ CD33 MyD88 MyD88FcεRIβ CD33 MyD88 MyD88 FcεRIγ CD33 MyD88 MyD88 DAP10 CD33 MyD88 MyD88DAP12 CD33 MyD88 MyD88 CD32 CD33 MyD88 MyD88 CD79a CD33 MyD88 MyD88CD79b CD33 MyD88 CD7 CD8 CD33 MyD88 CD7 CD3ζ CD33 MyD88 CD7 CD3δ CD33MyD88 CD7 CD3γ CD33 MyD88 CD7 CD3ε CD33 MyD88 CD7 FcγRI-γ CD33 MyD88 CD7FcγRIII-γ CD33 MyD88 CD7 FcεRIβ CD33 MyD88 CD7 FcεRIγ CD33 MyD88 CD7DAP10 CD33 MyD88 CD7 DAP12 CD33 MyD88 CD7 CD32 CD33 MyD88 CD7 CD79a CD33MyD88 CD7 CD79b CD33 MyD88 BTNL3 CD8 CD33 MyD88 BTNL3 CD3ζ CD33 MyD88BTNL3 CD3δ CD33 MyD88 BTNL3 CD3γ CD33 MyD88 BTNL3 CD3ε CD33 MyD88 BTNL3FcγRI-γ CD33 MyD88 BTNL3 FcγRIII-γ CD33 MyD88 BTNL3 FcεRIβ CD33 MyD88BTNL3 FcεRIγ CD33 MyD88 BTNL3 DAP10 CD33 MyD88 BTNL3 DAP12 CD33 MyD88BTNL3 CD32 CD33 MyD88 BTNL3 CD79a CD33 MyD88 BTNL3 CD79b CD33 MyD88NKG2D CD8 CD33 MyD88 NKG2D CD3ζ CD33 MyD88 NKG2D CD3δ CD33 MyD88 NKG2DCD3γ CD33 MyD88 NKG2D CD3ε CD33 MyD88 NKG2D FcγRI-γ CD33 MyD88 NKG2DFcγRIII-γ CD33 MyD88 NKG2D FcεRIβ CD33 MyD88 NKG2D FcεRIγ CD33 MyD88NKG2D DAP10 CD33 MyD88 NKG2D DAP12 CD33 MyD88 NKG2D CD32 CD33 MyD88NKG2D CD79a CD33 MyD88 NKG2D CD79b CD33 CD7 CD28 CD8 CD33 CD7 CD28 CD3ζCD33 CD7 CD28 CD3δ CD33 CD7 CD28 CD3γ CD33 CD7 CD28 CD3ε CD33 CD7 CD28FcγRI-γ CD33 CD7 CD28 FcγRIII-γ CD33 CD7 CD28 FcεRIβ CD33 CD7 CD28FcεRIγ CD33 CD7 CD28 DAP10 CD33 CD7 CD28 DAP12 CD33 CD7 CD28 CD32 CD33CD7 CD28 CD79a CD33 CD7 CD28 CD79b CD33 CD7 CD8 CD8 CD33 CD7 CD8 CD3ζCD33 CD7 CD8 CD3δ CD33 CD7 CD8 CD3γ CD33 CD7 CD8 CD3ε CD33 CD7 CD8FcγRI-γ CD33 CD7 CD8 FcγRIII-γ CD33 CD7 CD8 FcεRIβ CD33 CD7 CD8 FcεRIγCD33 CD7 CD8 DAP10 CD33 CD7 CD8 DAP12 CD33 CD7 CD8 CD32 CD33 CD7 CD8CD79a CD33 CD7 CD8 CD79b CD33 CD7 CD4 CD8 CD33 CD7 CD4 CD3ζ CD33 CD7 CD4CD3δ CD33 CD7 CD4 CD3γ CD33 CD7 CD4 CD3ε CD33 CD7 CD4 FcγRI-γ CD33 CD7CD4 FcγRIII-γ CD33 CD7 CD4 FcεRIβ CD33 CD7 CD4 FcεRIγ CD33 CD7 CD4 DAP10CD33 CD7 CD4 DAP12 CD33 CD7 CD4 CD32 CD33 CD7 CD4 CD79a CD33 CD7 CD4CD79b CD33 CD7 b2c CD8 CD33 CD7 b2c CD3ζ CD33 CD7 b2c CD3δ CD33 CD7 b2cCD3γ CD33 CD7 b2c CD3ε CD33 CD7 b2c FcγRI-γ CD33 CD7 b2c FcγRIII-γ CD33CD7 b2c FcεRIβ CD33 CD7 b2c FcεRIγ CD33 CD7 b2c DAP10 CD33 CD7 b2c DAP12CD33 CD7 b2c CD32 CD33 CD7 b2c CD79a CD33 CD7 b2c CD79b CD33 CD7CD137/41BB CD8 CD33 CD7 CD137/41BB CD3ζ CD33 CD7 CD137/41BB CD3δ CD33CD7 CD137/41BB CD3γ CD33 CD7 CD137/41BB CD3ε CD33 CD7 CD137/41BB FcγRI-γCD33 CD7 CD137/41BB FcγRIII-γ CD33 CD7 CD137/41BB FcεRIβ CD33 CD7CD137/41BB FcεRIγ CD33 CD7 CD137/41BB DAP10 CD33 CD7 CD137/41BB DAP12CD33 CD7 CD137/41BB CD32 CD33 CD7 CD137/41BB CD79a CD33 CD7 CD137/41BBCD79b CD33 CD7 ICOS CD8 CD33 CD7 ICOS CD3ζ CD33 CD7 ICOS CD3δ CD33 CD7ICOS CD3γ CD33 CD7 ICOS CD3ε CD33 CD7 ICOS FcγRI-γ CD33 CD7 ICOSFcγRIII-γ CD33 CD7 ICOS FcεRIβ CD33 CD7 ICOS FcεRIγ CD33 CD7 ICOS DAP10CD33 CD7 ICOS DAP12 CD33 CD7 ICOS CD32 CD33 CD7 ICOS CD79a CD33 CD7 ICOSCD79b CD33 CD7 CD27 CD8 CD33 CD7 CD27 CD3ζ CD33 CD7 CD27 CD3δ CD33 CD7CD27 CD3γ CD33 CD7 CD27 CD3ε CD33 CD7 CD27 FcγRI-γ CD33 CD7 CD27FcγRIII-γ CD33 CD7 CD27 FcεRIβ CD33 CD7 CD27 FcεRIγ CD33 CD7 CD27 DAP10CD33 CD7 CD27 DAP12 CD33 CD7 CD27 CD32 CD33 CD7 CD27 CD79a CD33 CD7 CD27CD79b CD33 CD7 CD28δ CD8 CD33 CD7 CD28δ CD3ζ CD33 CD7 CD28δ CD3δ CD33CD7 CD28δ CD3γ CD33 CD7 CD28δ CD3ε CD33 CD7 CD28δ FcγRI-γ CD33 CD7 CD28δFcγRIII-γ CD33 CD7 CD28δ FcεRIβ CD33 CD7 CD28δ FcεRIγ CD33 CD7 CD28δDAP10 CD33 CD7 CD28δ DAP12 CD33 CD7 CD28δ CD32 CD33 CD7 CD28δ CD79a CD33CD7 CD28δ CD79b CD33 CD7 CD80 CD8 CD33 CD7 CD80 CD3ζ CD33 CD7 CD80 CD3δCD33 CD7 CD80 CD3γ CD33 CD7 CD80 CD3ε CD33 CD7 CD80 FcγRI-γ CD33 CD7CD80 FcγRIII-γ CD33 CD7 CD80 FcεRIβ CD33 CD7 CD80 FcεRIγ CD33 CD7 CD80DAP10 CD33 CD7 CD80 DAP12 CD33 CD7 CD80 CD32 CD33 CD7 CD80 CD79a CD33CD7 CD80 CD79b CD33 CD7 CD86 CD8 CD33 CD7 CD86 CD3ζ CD33 CD7 CD86 CD3δCD33 CD7 CD86 CD3γ CD33 CD7 CD86 CD3ε CD33 CD7 CD86 FcγRI-γ CD33 CD7CD86 FcγRIII-γ CD33 CD7 CD86 FcεRIβ CD33 CD7 CD86 FcεRIγ CD33 CD7 CD86DAP10 CD33 CD7 CD86 DAP12 CD33 CD7 CD86 CD32 CD33 CD7 CD86 CD79a CD33CD7 CD86 CD79b CD33 CD7 OX40 CD8 CD33 CD7 OX40 CD3ζ CD33 CD7 OX40 CD3δCD33 CD7 OX40 CD3γ CD33 CD7 OX40 CD3ε CD33 CD7 OX40 FcγRI-γ CD33 CD7OX40 FcγRIII-γ CD33 CD7 OX40 FcεRIβ CD33 CD7 OX40 FcεRIγ CD33 CD7 OX40DAP10 CD33 CD7 OX40 DAP12 CD33 CD7 OX40 CD32 CD33 CD7 OX40 CD79a CD33CD7 OX40 CD79b CD33 CD7 DAP10 CD8 CD33 CD7 DAP10 CD3ζ CD33 CD7 DAP10CD3δ CD33 CD7 DAP10 CD3γ CD33 CD7 DAP10 CD3ε CD33 CD7 DAP10 FcγRI-γ CD33CD7 DAP10 FcγRIII-γ CD33 CD7 DAP10 FcεRIβ CD33 CD7 DAP10 FcεRIγ CD33 CD7DAP10 DAP10 CD33 CD7 DAP10 DAP12 CD33 CD7 DAP10 CD32 CD33 CD7 DAP10CD79a CD33 CD7 DAP10 CD79b CD33 CD7 DAP12 CD8 CD33 CD7 DAP12 CD3ζ CD33CD7 DAP12 CD3δ CD33 CD7 DAP12 CD3γ CD33 CD7 DAP12 CD3ε CD33 CD7 DAP12FcγRI-γ CD33 CD7 DAP12 FcγRIII-γ CD33 CD7 DAP12 FcεRIβ CD33 CD7 DAP12FcεRIγ CD33 CD7 DAP12 DAP10 CD33 CD7 DAP12 DAP12 CD33 CD7 DAP12 CD32CD33 CD7 DAP12 CD79a CD33 CD7 DAP12 CD79b CD33 CD7 MyD88 CD8 CD33 CD7MyD88 CD3ζ CD33 CD7 MyD88 CD3δ CD33 CD7 MyD88 CD3γ CD33 CD7 MyD88 CD3εCD33 CD7 MyD88 FcγRI-γ CD33 CD7 MyD88 FcγRIII-γ CD33 CD7 MyD88 FcεRIβCD33 CD7 MyD88 FcεRIγ CD33 CD7 MyD88 DAP10 CD33 CD7 MyD88 DAP12 CD33 CD7MyD88 CD32 CD33 CD7 MyD88 CD79a CD33 CD7 MyD88 CD79b CD33 CD7 CD7 CD8CD33 CD7 CD7 CD3ζ CD33 CD7 CD7 CD3δ CD33 CD7 CD7 CD3γ CD33 CD7 CD7 CD3εCD33 CD7 CD7 FcγRI-γ CD33 CD7 CD7 FcγRIII-γ CD33 CD7 CD7 FcεRIβ CD33 CD7CD7 FcεRIγ CD33 CD7 CD7 DAP10 CD33 CD7 CD7 DAP12 CD33 CD7 CD7 CD32 CD33CD7 CD7 CD79a CD33 CD7 CD7 CD79b CD33 CD7 BTNL3 CD8 CD33 CD7 BTNL3 CD3ζCD33 CD7 BTNL3 CD3δ CD33 CD7 BTNL3 CD3γ CD33 CD7 BTNL3 CD3ε CD33 CD7BTNL3 FcγRI-γ CD33 CD7 BTNL3 FcγRIII-γ CD33 CD7 BTNL3 FcεRIβ CD33 CD7BTNL3 FcεRIγ CD33 CD7 BTNL3 DAP10 CD33 CD7 BTNL3 DAP12 CD33 CD7 BTNL3CD32 CD33 CD7 BTNL3 CD79a CD33 CD7 BTNL3 CD79b CD33 CD7 NKG2D CD8 CD33CD7 NKG2D CD3ζ CD33 CD7 NKG2D CD3δ CD33 CD7 NKG2D CD3γ CD33 CD7 NKG2DCD3ε CD33 CD7 NKG2D FcγRI-γ CD33 CD7 NKG2D FcγRIII-γ CD33 CD7 NKG2DFcεRIβ CD33 CD7 NKG2D FcεRIγ CD33 CD7 NKG2D DAP10 CD33 CD7 NKG2D DAP12CD33 CD7 NKG2D CD32 CD33 CD7 NKG2D CD79a CD33 CD7 NKG2D CD79b CD33 BTNL3CD28 CD8 CD33 BTNL3 CD28 CD3ζ CD33 BTNL3 CD28 CD3δ CD33 BTNL3 CD28 CD3γCD33 BTNL3 CD28 CD3ε CD33 BTNL3 CD28 FcγRI-γ CD33 BTNL3 CD28 FcγRIII-γCD33 BTNL3 CD28 FcεRIβ CD33 BTNL3 CD28 FcεRIγ CD33 BTNL3 CD28 DAP10 CD33BTNL3 CD28 DAP12 CD33 BTNL3 CD28 CD32 CD33 BTNL3 CD28 CD79a CD33 BTNL3CD28 CD79b CD33 BTNL3 CD8 CD8 CD33 BTNL3 CD8 CD3ζ CD33 BTNL3 CD8 CD3δCD33 BTNL3 CD8 CD3γ CD33 BTNL3 CD8 CD3ε CD33 BTNL3 CD8 FcγRI-γ CD33BTNL3 CD8 FcγRIII-γ CD33 BTNL3 CD8 FcεRIβ CD33 BTNL3 CD8 FcεRIγ CD33BTNL3 CD8 DAP10 CD33 BTNL3 CD8 DAP12 CD33 BTNL3 CD8 CD32 CD33 BTNL3 CD8CD79a CD33 BTNL3 CD8 CD79b CD33 BTNL3 CD4 CD8 CD33 BTNL3 CD4 CD3ζ CD33BTNL3 CD4 CD3δ CD33 BTNL3 CD4 CD3γ CD33 BTNL3 CD4 CD3ε CD33 BTNL3 CD4FcγRI-γ CD33 BTNL3 CD4 FcγRIII-γ CD33 BTNL3 CD4 FcεRIβ CD33 BTNL3 CD4FcεRIγ CD33 BTNL3 CD4 DAP10 CD33 BTNL3 CD4 DAP12 CD33 BTNL3 CD4 CD32CD33 BTNL3 CD4 CD79a CD33 BTNL3 CD4 CD79b CD33 BTNL3 b2c CD8 CD33 BTNL3b2c CD3ζ CD33 BTNL3 b2c CD3δ CD33 BTNL3 b2c CD3γ CD33 BTNL3 b2c CD3εCD33 BTNL3 b2c FcγRI-γ CD33 BTNL3 b2c FcγRIII-γ CD33 BTNL3 b2c FcεRIβCD33 BTNL3 b2c FcεRIγ CD33 BTNL3 b2c DAP10 CD33 BTNL3 b2c DAP12 CD33BTNL3 b2c CD32 CD33 BTNL3 b2c CD79a CD33 BTNL3 b2c CD79b CD33 BTNL3CD137/41BB CD8 CD33 BTNL3 CD137/41BB CD3ζ CD33 BTNL3 CD137/41BB CD3δCD33 BTNL3 CD137/41BB CD3γ CD33 BTNL3 CD137/41BB CD3ε CD33 BTNL3CD137/41BB FcγRI-γ CD33 BTNL3 CD137/41BB FcγRIII-γ CD33 BTNL3 CD137/41BBFcεRIβ CD33 BTNL3 CD137/41BB FcεRIγ CD33 BTNL3 CD137/41BB DAP10 CD33BTNL3 CD137/41BB DAP12 CD33 BTNL3 CD137/41BB CD32 CD33 BTNL3 CD137/41BBCD79a CD33 BTNL3 CD137/41BB CD79b CD33 BTNL3 ICOS CD8 CD33 BTNL3 ICOSCD3ζ CD33 BTNL3 ICOS CD3δ CD33 BTNL3 ICOS CD3γ CD33 BTNL3 ICOS CD3ε CD33BTNL3 ICOS FcγRI-γ CD33 BTNL3 ICOS FcγRIII-γ CD33 BTNL3 ICOS FcεRIβ CD33BTNL3 ICOS FcεRIγ CD33 BTNL3 ICOS DAP10 CD33 BTNL3 ICOS DAP12 CD33 BTNL3ICOS CD32 CD33 BTNL3 ICOS CD79a CD33 BTNL3 ICOS CD79b CD33 BTNL3 CD27CD8 CD33 BTNL3 CD27 CD3ζ CD33 BTNL3 CD27 CD3δ CD33 BTNL3 CD27 CD3γ CD33BTNL3 CD27 CD3ε CD33 BTNL3 CD27 FcγRI-γ CD33 BTNL3 CD27 FcγRIII-γ CD33BTNL3 CD27 FcεRIβ CD33 BTNL3 CD27 FcεRIγ CD33 BTNL3 CD27 DAP10 CD33BTNL3 CD27 DAP12 CD33 BTNL3 CD27 CD32 CD33 BTNL3 CD27 CD79a CD33 BTNL3CD27 CD79b CD33 BTNL3 CD28δ CD8 CD33 BTNL3 CD28δ CD3ζ CD33 BTNL3 CD28δCD3δ CD33 BTNL3 CD28δ CD3γ CD33 BTNL3 CD28δ CD3ε CD33 BTNL3 CD28δFcγRI-γ CD33 BTNL3 CD28δ FcγRIII-γ CD33 BTNL3 CD28δ FcεRIβ CD33 BTNL3CD28δ FcεRIγ CD33 BTNL3 CD28δ DAP10 CD33 BTNL3 CD28δ DAP12 CD33 BTNL3CD28δ CD32 CD33 BTNL3 CD28δ CD79a CD33 BTNL3 CD28δ CD79b CD33 BTNL3 CD80CD8 CD33 BTNL3 CD80 CD3ζ CD33 BTNL3 CD80 CD3δ CD33 BTNL3 CD80 CD3γ CD33BTNL3 CD80 CD3ε CD33 BTNL3 CD80 FcγRI-γ CD33 BTNL3 CD80 FcγRIII-γ CD33BTNL3 CD80 FcεRIβ CD33 BTNL3 CD80 FcεRIγ CD33 BTNL3 CD80 DAP10 CD33BTNL3 CD80 DAP12 CD33 BTNL3 CD80 CD32 CD33 BTNL3 CD80 CD79a CD33 BTNL3CD80 CD79b CD33 BTNL3 CD86 CD8 CD33 BTNL3 CD86 CD3ζ CD33 BTNL3 CD86 CD3δCD33 BTNL3 CD86 CD3γ CD33 BTNL3 CD86 CD3ε CD33 BTNL3 CD86 FcγRI-γ CD33BTNL3 CD86 FcγRIII-γ CD33 BTNL3 CD86 FcεRIβ CD33 BTNL3 CD86 FcεRIγ CD33BTNL3 CD86 DAP10 CD33 BTNL3 CD86 DAP12 CD33 BTNL3 CD86 CD32 CD33 BTNL3CD86 CD79a CD33 BTNL3 CD86 CD79b CD33 BTNL3 OX40 CD8 CD33 BTNL3 OX40CD3ζ CD33 BTNL3 OX40 CD3δ CD33 BTNL3 OX40 CD3γ CD33 BTNL3 OX40 CD3ε CD33BTNL3 OX40 FcγRI-γ CD33 BTNL3 OX40 FcγRIII-γ CD33 BTNL3 OX40 FcεRIβ CD33BTNL3 OX40 FcεRIγ CD33 BTNL3 OX40 DAP10 CD33 BTNL3 OX40 DAP12 CD33 BTNL3OX40 CD32 CD33 BTNL3 OX40 CD79a CD33 BTNL3 OX40 CD79b CD33 BTNL3 DAP10CD8 CD33 BTNL3 DAP10 CD3ζ CD33 BTNL3 DAP10 CD3δ CD33 BTNL3 DAP10 CD3γCD33 BTNL3 DAP10 CD3ε CD33 BTNL3 DAP10 FcγRI-γ CD33 BTNL3 DAP10FcγRIII-γ CD33 BTNL3 DAP10 FcεRIβ CD33 BTNL3 DAP10 FcεRIγ CD33 BTNL3DAP10 DAP10 CD33 BTNL3 DAP10 DAP12 CD33 BTNL3 DAP10 CD32 CD33 BTNL3DAP10 CD79a CD33 BTNL3 DAP10 CD79b CD33 BTNL3 DAP12 CD8 CD33 BTNL3 DAP12CD3ζ CD33 BTNL3 DAP12 CD3δ CD33 BTNL3 DAP12 CD3γ CD33 BTNL3 DAP12 CD3εCD33 BTNL3 DAP12 FcγRI-γ CD33 BTNL3 DAP12 FcγRIII-γ CD33 BTNL3 DAP12FcεRIβ CD33 BTNL3 DAP12 FcεRIγ CD33 BTNL3 DAP12 DAP10 CD33 BTNL3 DAP12DAP12 CD33 BTNL3 DAP12 CD32 CD33 BTNL3 DAP12 CD79a CD33 BTNL3 DAP12CD79b CD33 BTNL3 MyD88 CD8 CD33 BTNL3 MyD88 CD3ζ CD33 BTNL3 MyD88 CD3δCD33 BTNL3 MyD88 CD3γ CD33 BTNL3 MyD88 CD3ε CD33 BTNL3 MyD88 FcγRI-γCD33 BTNL3 MyD88 FcγRIII-γ CD33 BTNL3 MyD88 FcεRIβ CD33 BTNL3 MyD88FcεRIγ CD33 BTNL3 MyD88 DAP10 CD33 BTNL3 MyD88 DAP12 CD33 BTNL3 MyD88CD32 CD33 BTNL3 MyD88 CD79a CD33 BTNL3 MyD88 CD79b CD33 BTNL3 CD7 CD8CD33 BTNL3 CD7 CD3ζ CD33 BTNL3 CD7 CD3δ CD33 BTNL3 CD7 CD3γ CD33 BTNL3CD7 CD3ε CD33 BTNL3 CD7 FcγRI-γ CD33 BTNL3 CD7 FcγRIII-γ CD33 BTNL3 CD7FcεRIβ CD33 BTNL3 CD7 FcεRIγ CD33 BTNL3 CD7 DAP10 CD33 BTNL3 CD7 DAP12CD33 BTNL3 CD7 CD32 CD33 BTNL3 CD7 CD79a CD33 BTNL3 CD7 CD79b CD33 BTNL3BTNL3 CD8 CD33 BTNL3 BTNL3 CD3ζ CD33 BTNL3 BTNL3 CD3δ CD33 BTNL3 BTNL3CD3γ CD33 BTNL3 BTNL3 CD3ε CD33 BTNL3 BTNL3 FcγRI-γ CD33 BTNL3 BTNL3FcγRIII-γ CD33 BTNL3 BTNL3 FcεRIβ CD33 BTNL3 BTNL3 FcεRIγ CD33 BTNL3BTNL3 DAP10 CD33 BTNL3 BTNL3 DAP12 CD33 BTNL3 BTNL3 CD32 CD33 BTNL3BTNL3 CD79a CD33 BTNL3 BTNL3 CD79b CD33 BTNL3 NKG2D CD8 CD33 BTNL3 NKG2DCD3ζ CD33 BTNL3 NKG2D CD3δ CD33 BTNL3 NKG2D CD3γ CD33 BTNL3 NKG2D CD3εCD33 BTNL3 NKG2D FcγRI-γ CD33 BTNL3 NKG2D FcγRIII-γ CD33 BTNL3 NKG2DFcεRIβ CD33 BTNL3 NKG2D FcεRIγ CD33 BTNL3 NKG2D DAP10 CD33 BTNL3 NKG2DDAP12 CD33 BTNL3 NKG2D CD32 CD33 BTNL3 NKG2D CD79a CD33 BTNL3 NKG2DCD79b CD33 NKG2D CD28 CD8 CD33 NKG2D CD28 CD3ζ CD33 NKG2D CD28 CD3δ CD33NKG2D CD28 CD3γ CD33 NKG2D CD28 CD3ε CD33 NKG2D CD28 FcγRI-γ CD33 NKG2DCD28 FcγRIII-γ CD33 NKG2D CD28 FcεRIβ CD33 NKG2D CD28 FcεRIγ CD33 NKG2DCD28 DAP10 CD33 NKG2D CD28 DAP12 CD33 NKG2D CD28 CD32 CD33 NKG2D CD28CD79a CD33 NKG2D CD28 CD79b CD33 NKG2D CD8 CD8 CD33 NKG2D CD8 CD3ζ CD33NKG2D CD8 CD3δ CD33 NKG2D CD8 CD3γ CD33 NKG2D CD8 CD3ε CD33 NKG2D CD8FcγRI-γ CD33 NKG2D CD8 FcγRIII-γ CD33 NKG2D CD8 FcεRIβ CD33 NKG2D CD8FcεRIγ CD33 NKG2D CD8 DAP10 CD33 NKG2D CD8 DAP12 CD33 NKG2D CD8 CD32CD33 NKG2D CD8 CD79a CD33 NKG2D CD8 CD79b CD33 NKG2D CD4 CD8 CD33 NKG2DCD4 CD3ζ CD33 NKG2D CD4 CD3δ CD33 NKG2D CD4 CD3γ CD33 NKG2D CD4 CD3εCD33 NKG2D CD4 FcγRI-γ CD33 NKG2D CD4 FcγRIII-γ CD33 NKG2D CD4 FcεRIβCD33 NKG2D CD4 FcεRIγ CD33 NKG2D CD4 DAP10 CD33 NKG2D CD4 DAP12 CD33NKG2D CD4 CD32 CD33 NKG2D CD4 CD79a CD33 NKG2D CD4 CD79b CD33 NKG2D b2cCD8 CD33 NKG2D b2c CD3ζ CD33 NKG2D b2c CD3δ CD33 NKG2D b2c CD3γ CD33NKG2D b2c CD3ε CD33 NKG2D b2c FcγRI-γ CD33 NKG2D b2c FcγRIII-γ CD33NKG2D b2c FcεRIβ CD33 NKG2D b2c FcεRIγ CD33 NKG2D b2c DAP10 CD33 NKG2Db2c DAP12 CD33 NKG2D b2c CD32 CD33 NKG2D b2c CD79a CD33 NKG2D b2c CD79bCD33 NKG2D CD137/41BB CD8 CD33 NKG2D CD137/41BB CD3ζ CD33 NKG2DCD137/41BB CD3δ CD33 NKG2D CD137/41BB CD3γ CD33 NKG2D CD137/41BB CD3εCD33 NKG2D CD137/41BB FcγRI-γ CD33 NKG2D CD137/41BB FcγRIII-γ CD33 NKG2DCD137/41BB FcεRIβ CD33 NKG2D CD137/41BB FcεRIγ CD33 NKG2D CD137/41BBDAP10 CD33 NKG2D CD137/41BB DAP12 CD33 NKG2D CD137/41BB CD32 CD33 NKG2DCD137/41BB CD79a CD33 NKG2D CD137/41BB CD79b CD33 NKG2D ICOS CD8 CD33NKG2D ICOS CD3ζ CD33 NKG2D ICOS CD3δ CD33 NKG2D ICOS CD3γ CD33 NKG2DICOS CD3ε CD33 NKG2D ICOS FcγRI-γ CD33 NKG2D ICOS FcγRIII-γ CD33 NKG2DICOS FcεRIβ CD33 NKG2D ICOS FcεRIγ CD33 NKG2D ICOS DAP10 CD33 NKG2D ICOSDAP12 CD33 NKG2D ICOS CD32 CD33 NKG2D ICOS CD79a CD33 NKG2D ICOS CD79bCD33 NKG2D CD27 CD8 CD33 NKG2D CD27 CD3ζ CD33 NKG2D CD27 CD3δ CD33 NKG2DCD27 CD3γ CD33 NKG2D CD27 CD3ε CD33 NKG2D CD27 FcγRI-γ CD33 NKG2D CD27FcγRIII-γ CD33 NKG2D CD27 FcεRIβ CD33 NKG2D CD27 FcεRIγ CD33 NKG2D CD27DAP10 CD33 NKG2D CD27 DAP12 CD33 NKG2D CD27 CD32 CD33 NKG2D CD27 CD79aCD33 NKG2D CD27 CD79b CD33 NKG2D CD28δ CD8 CD33 NKG2D CD28δ CD3ζ CD33NKG2D CD28δ CD3δ CD33 NKG2D CD28δ CD3γ CD33 NKG2D CD28δ CD3ε CD33 NKG2DCD28δ FcγRI-γ CD33 NKG2D CD28δ FcγRIII-γ CD33 NKG2D CD28δ FcεRIβ CD33NKG2D CD28δ FcεRIγ CD33 NKG2D CD28δ DAP10 CD33 NKG2D CD28δ DAP12 CD33NKG2D CD28δ CD32 CD33 NKG2D CD28δ CD79a CD33 NKG2D CD28δ CD79b CD33NKG2D CD80 CD8 CD33 NKG2D CD80 CD3ζ CD33 NKG2D CD80 CD3δ CD33 NKG2D CD80CD3γ CD33 NKG2D CD80 CD3ε CD33 NKG2D CD80 FcγRI-γ CD33 NKG2D CD80FcγRIII-γ CD33 NKG2D CD80 FcεRIβ CD33 NKG2D CD80 FcεRIγ CD33 NKG2D CD80DAP10 CD33 NKG2D CD80 DAP12 CD33 NKG2D CD80 CD32 CD33 NKG2D CD80 CD79aCD33 NKG2D CD80 CD79b CD33 NKG2D CD86 CD8 CD33 NKG2D CD86 CD3ζ CD33NKG2D CD86 CD3δ CD33 NKG2D CD86 CD3γ CD33 NKG2D CD86 CD3ε CD33 NKG2DCD86 FcγRI-γ CD33 NKG2D CD86 FcγRIII-γ CD33 NKG2D CD86 FcεRIβ CD33 NKG2DCD86 FcεRIγ CD33 NKG2D CD86 DAP10 CD33 NKG2D CD86 DAP12 CD33 NKG2D CD86CD32 CD33 NKG2D CD86 CD79a CD33 NKG2D CD86 CD79b CD33 NKG2D OX40 CD8CD33 NKG2D OX40 CD3ζ CD33 NKG2D OX40 CD3δ CD33 NKG2D OX40 CD3γ CD33NKG2D OX40 CD3ε CD33 NKG2D OX40 FcγRI-γ CD33 NKG2D OX40 FcγRIII-γ CD33NKG2D OX40 FcεRIβ CD33 NKG2D OX40 FcεRIγ CD33 NKG2D OX40 DAP10 CD33NKG2D OX40 DAP12 CD33 NKG2D OX40 CD32 CD33 NKG2D OX40 CD79a CD33 NKG2DOX40 CD79b CD33 NKG2D DAP10 CD8 CD33 NKG2D DAP10 CD3ζ CD33 NKG2D DAP10CD3δ CD33 NKG2D DAP10 CD3γ CD33 NKG2D DAP10 CD3ε CD33 NKG2D DAP10FcγRI-γ CD33 NKG2D DAP10 FcγRIII-γ CD33 NKG2D DAP10 FcεRIβ CD33 NKG2DDAP10 FcεRIγ CD33 NKG2D DAP10 DAP10 CD33 NKG2D DAP10 DAP12 CD33 NKG2DDAP10 CD32 CD33 NKG2D DAP10 CD79a CD33 NKG2D DAP10 CD79b CD33 NKG2DDAP12 CD8 CD33 NKG2D DAP12 CD3ζ CD33 NKG2D DAP12 CD3δ CD33 NKG2D DAP12CD3γ CD33 NKG2D DAP12 CD3ε CD33 NKG2D DAP12 FcγRI-γ CD33 NKG2D DAP12FcγRIII-γ CD33 NKG2D DAP12 FcεRIβ CD33 NKG2D DAP12 FcεRIγ CD33 NKG2DDAP12 DAP10 CD33 NKG2D DAP12 DAP12 CD33 NKG2D DAP12 CD32 CD33 NKG2DDAP12 CD79a CD33 NKG2D DAP12 CD79b CD33 NKG2D MyD88 CD8 CD33 NKG2D MyD88CD3ζ CD33 NKG2D MyD88 CD3δ CD33 NKG2D MyD88 CD3γ CD33 NKG2D MyD88 CD3εCD33 NKG2D MyD88 FcγRI-γ CD33 NKG2D MyD88 FcγRIII-γ CD33 NKG2D MyD88FcεRIβ CD33 NKG2D MyD88 FcεRIγ CD33 NKG2D MyD88 DAP10 CD33 NKG2D MyD88DAP12 CD33 NKG2D MyD88 CD32 CD33 NKG2D MyD88 CD79a CD33 NKG2D MyD88CD79b CD33 NKG2D CD7 CD8 CD33 NKG2D CD7 CD3ζ CD33 NKG2D CD7 CD3δ CD33NKG2D CD7 CD3γ CD33 NKG2D CD7 CD3ε CD33 NKG2D CD7 FcγRI-γ CD33 NKG2D CD7FcγRIII-γ CD33 NKG2D CD7 FcεRIβ CD33 NKG2D CD7 FcεRIγ CD33 NKG2D CD7DAP10 CD33 NKG2D CD7 DAP12 CD33 NKG2D CD7 CD32 CD33 NKG2D CD7 CD79a CD33NKG2D CD7 CD79b CD33 NKG2D BTNL3 CD8 CD33 NKG2D BTNL3 CD3ζ CD33 NKG2DBTNL3 CD3δ CD33 NKG2D BTNL3 CD3γ CD33 NKG2D BTNL3 CD3ε CD33 NKG2D BTNL3FcγRI-γ CD33 NKG2D BTNL3 FcγRIII-γ CD33 NKG2D BTNL3 FcεRIβ CD33 NKG2DBTNL3 FcεRIγ CD33 NKG2D BTNL3 DAP10 CD33 NKG2D BTNL3 DAP12 CD33 NKG2DBTNL3 CD32 CD33 NKG2D BTNL3 CD79a CD33 NKG2D BTNL3 CD79b CD33 NKG2DNKG2D CD8 CD33 NKG2D NKG2D CD3ζ CD33 NKG2D NKG2D CD3δ CD33 NKG2D NKG2DCD3γ CD33 NKG2D NKG2D CD3ε CD33 NKG2D NKG2D FcγRI-γ CD33 NKG2D NKG2DFcγRIII-γ CD33 NKG2D NKG2D FcεRIβ CD33 NKG2D NKG2D FcεRIγ CD33 NKG2DNKG2D DAP10 CD33 NKG2D NKG2D DAP12 CD33 NKG2D NKG2D CD32 CD33 NKG2DNKG2D CD79a CD33 NKG2D NKG2D CD79b

TABLE 4 CARs lacking Co-Simulatory Signal (for dual CAR approach) ScFvCo-stimulatory Signal Signal Domain CD33 none CD8 CD33 none CD3ζ CD33none CD3δ CD33 none CD3γ CD33 none CD3ε CD33 none FcγRI-γ CD33 noneFcyRIII-γ CD33 none FcεRIβ CD33 none FcεRIγ CD33 none DAP10 CD33 noneDAP12 CD33 none CD32 CD33 none CD79a CD33 none CD8 CD33 none CD3ζ CD33none CD3δ CD33 none CD3γ CD33 none CD3ε CD33 none FcγRI-γ

TABLE 5 CARs lacking Signal Domain (for dual CAR approach) ScFvCo-stimulatory Signal Signal Domain CD33 CD28 none CD33 CD8 none CD33CD4 none CD33 b2c none CD33 CD137/41BB none CD33 ICOS none CD33 CD27none CD33 CD28δ none CD33 CD80 none CD33 CD86 none CD33 OX40 none CD33DAP10 none CD33 MyD88 none CD33 CD7 none CD33 DAP12 none CD33 MyD88 noneCD33 CD7 none CD33 BTNL3 none CD33 NKG2D none

TABLE 6 Third Generation CARs lacking Signal Domain (for dual CARapproach) Co-stimulatory Co-stimulatory Signal ScFv Signal Signal DomainCD33 CD28 CD28 none CD33 CD28 CD8 none CD33 CD28 CD4 none CD33 CD28 b2cnone CD33 CD28 CD137/41BB none CD33 CD28 ICOS none CD33 CD28 CD27 noneCD33 CD28 CD28δ none CD33 CD28 CD80 none CD33 CD28 CD86 none CD33 CD28OX40 none CD33 CD28 DAP10 none CD33 CD28 MyD88 none CD33 CD28 CD7 noneCD33 CD28 DAP12 none CD33 CD28 MyD88 none CD33 CD28 CD7 none CD33 CD8CD28 none CD33 CD8 CD8 none CD33 CD8 CD4 none CD33 CD8 b2c none CD33 CD8CD137/41BB none CD33 CD8 ICOS none CD33 CD8 CD27 none CD33 CD8 CD28δnone CD33 CD8 CD80 none CD33 CD8 CD86 none CD33 CD8 OX40 none CD33 CD8DAP10 none CD33 CD8 MyD88 none CD33 CD8 CD7 none CD33 CD8 DAP12 noneCD33 CD8 MyD88 none CD33 CD8 CD7 none CD33 CD4 CD28 none CD33 CD4 CD8none CD33 CD4 CD4 none CD33 CD4 b2c none CD33 CD4 CD137/41BB none CD33CD4 ICOS none CD33 CD4 CD27 none CD33 CD4 CD28δ none CD33 CD4 CD80 noneCD33 CD4 CD86 none CD33 CD4 OX40 none CD33 CD4 DAP10 none CD33 CD4 MyD88none CD33 CD4 CD7 none CD33 CD4 DAP12 none CD33 CD4 MyD88 none CD33 CD4CD7 none CD33 b2c CD28 none CD33 b2c CD8 none CD33 b2c CD4 none CD33 b2cb2c none CD33 b2c CD137/41BB none CD33 b2c ICOS none CD33 b2c CD27 noneCD33 b2c CD28δ none CD33 b2c CD80 none CD33 b2c CD86 none CD33 b2c OX40none CD33 b2c DAP10 none CD33 b2c MyD88 none CD33 b2c CD7 none CD33 b2cDAP12 none CD33 b2c MyD88 none CD33 b2c CD7 none CD33 CD137/41BB CD28none CD33 CD137/41BB CD8 none CD33 CD137/41BB CD4 none CD33 CD137/41BBb2c none CD33 CD137/41BB CD137/41BB none CD33 CD137/41BB ICOS none CD33CD137/41BB CD27 none CD33 CD137/41BB CD28δ none CD33 CD137/41BB CD80none CD33 CD137/41BB CD86 none CD33 CD137/41BB OX40 none CD33 CD137/41BBDAP10 none CD33 CD137/41BB MyD88 none CD33 CD137/41BB CD7 none CD33CD137/41BB DAP12 none CD33 CD137/41BB MyD88 none CD33 CD137/41BB CD7none CD33 ICOS CD28 none CD33 ICOS CD8 none CD33 ICOS CD4 none CD33 ICOSb2c none CD33 ICOS CD137/41BB none CD33 ICOS ICOS none CD33 ICOS CD27none CD33 ICOS CD28δ none CD33 ICOS CD80 none CD33 ICOS CD86 none CD33ICOS OX40 none CD33 ICOS DAP10 none CD33 ICOS MyD88 none CD33 ICOS CD7none CD33 ICOS DAP12 none CD33 ICOS MyD88 none CD33 ICOS CD7 none CD33ICOS CD28 none CD33 ICOS CD8 none CD33 ICOS CD4 none CD33 ICOS b2c noneCD33 ICOS CD137/41BB none CD33 ICOS ICOS none CD33 ICOS CD27 none CD33ICOS CD28δ none CD33 ICOS CD80 none CD33 ICOS CD86 none CD33 ICOS OX40none CD33 ICOS DAP10 none CD33 ICOS MyD88 none CD33 ICOS CD7 none CD33ICOS DAP12 none CD33 ICOS MyD88 none CD33 ICOS CD7 none CD33 CD27 CD28none CD33 CD27 CD8 none CD33 CD27 CD4 none CD33 CD27 b2c none CD33 CD27CD137/41BB none CD33 CD27 ICOS none CD33 CD27 CD27 none CD33 CD27 CD28δnone CD33 CD27 CD80 none CD33 CD27 CD86 none CD33 CD27 OX40 none CD33CD27 DAP10 none CD33 CD27 MyD88 none CD33 CD27 CD7 none CD33 CD27 DAP12none CD33 CD27 MyD88 none CD33 CD27 CD7 none CD33 CD28δ CD28 none CD33CD28δ CD8 none CD33 CD28δ CD4 none CD33 CD28δ b2c none CD33 CD28δCD137/41BB none CD33 CD28δ ICOS none CD33 CD28δ CD27 none CD33 CD28δCD28δ none CD33 CD28δ CD80 none CD33 CD28δ CD86 none CD33 CD28δ OX40none CD33 CD28δ DAP10 none CD33 CD28δ MyD88 none CD33 CD28δ CD7 noneCD33 CD28δ DAP12 none CD33 CD28δ MyD88 none CD33 CD28δ CD7 none CD33CD80 CD28 none CD33 CD80 CD8 none CD33 CD80 CD4 none CD33 CD80 b2c noneCD33 CD80 CD137/41BB none CD33 CD80 ICOS none CD33 CD80 CD27 none CD33CD80 CD28δ none CD33 CD80 CD80 none CD33 CD80 CD86 none CD33 CD80 OX40none CD33 CD80 DAP10 none CD33 CD80 MyD88 none CD33 CD80 CD7 none CD33CD80 DAP12 none CD33 CD80 MyD88 none CD33 CD80 CD7 none CD33 CD86 CD28none CD33 CD86 CD8 none CD33 CD86 CD4 none CD33 CD86 b2c none CD33 CD86CD137/41BB none CD33 CD86 ICOS none CD33 CD86 CD27 none CD33 CD86 CD28δnone CD33 CD86 CD80 none CD33 CD86 CD86 none CD33 CD86 OX40 none CD33CD86 DAP10 none CD33 CD86 MyD88 none CD33 CD86 CD7 none CD33 CD86 DAP12none CD33 CD86 MyD88 none CD33 CD86 CD7 none CD33 OX40 CD28 none CD33OX40 CD8 none CD33 OX40 CD4 none CD33 OX40 b2c none CD33 OX40 CD137/41BBnone CD33 OX40 ICOS none CD33 OX40 CD27 none CD33 OX40 CD28δ none CD33OX40 CD80 none CD33 OX40 CD86 none CD33 OX40 OX40 none CD33 OX40 DAP10none CD33 OX40 MyD88 none CD33 OX40 CD7 none CD33 OX40 DAP12 none CD33OX40 MyD88 none CD33 OX40 CD7 none CD33 DAP10 CD28 none CD33 DAP10 CD8none CD33 DAP10 CD4 none CD33 DAP10 b2c none CD33 DAP10 CD137/41BB noneCD33 DAP10 ICOS none CD33 DAP10 CD27 none CD33 DAP10 CD28δ none CD33DAP10 CD80 none CD33 DAP10 CD86 none CD33 DAP10 OX40 none CD33 DAP10DAP10 none CD33 DAP10 MyD88 none CD33 DAP10 CD7 none CD33 DAP10 DAP12none CD33 DAP10 MyD88 none CD33 DAP10 CD7 none CD33 DAP12 CD28 none CD33DAP12 CD8 none CD33 DAP12 CD4 none CD33 DAP12 b2c none CD33 DAP12CD137/41BB none CD33 DAP12 ICOS none CD33 DAP12 CD27 none CD33 DAP12CD28δ none CD33 DAP12 CD80 none CD33 DAP12 CD86 none CD33 DAP12 OX40none CD33 DAP12 DAP10 none CD33 DAP12 MyD88 none CD33 DAP12 CD7 noneCD33 DAP12 DAP12 none CD33 DAP12 MyD88 none CD33 DAP12 CD7 none CD33MyD88 CD28 none CD33 MyD88 CD8 none CD33 MyD88 CD4 none CD33 MyD88 b2cnone CD33 MyD88 CD137/41BB none CD33 MyD88 ICOS none CD33 MyD88 CD27none CD33 MyD88 CD28δ none CD33 MyD88 CD80 none CD33 MyD88 CD86 noneCD33 MyD88 OX40 none CD33 MyD88 DAP10 none CD33 MyD88 MyD88 none CD33MyD88 CD7 none CD33 MyD88 DAP12 none CD33 MyD88 MyD88 none CD33 MyD88CD7 none CD33 CD7 CD28 none CD33 CD7 CD8 none CD33 CD7 CD4 none CD33 CD7b2c none CD33 CD7 CD137/41BB none CD33 CD7 ICOS none CD33 CD7 CD27 noneCD33 CD7 CD28δ none CD33 CD7 CD80 none CD33 CD7 CD86 none CD33 CD7 OX40none CD33 CD7 DAP10 none CD33 CD7 MyD88 none CD33 CD7 CD7 none CD33 CD7DAP12 none CD33 CD7 MyD88 none CD33 CD7 CD7 none CD33 BTNL3 CD28 noneCD33 BTNL3 CD8 none CD33 BTNL3 CD4 none CD33 BTNL3 b2c none CD33 BTNL3CD137/41BB none CD33 BTNL3 ICOS none CD33 BTNL3 CD27 none CD33 BTNL3CD28δ none CD33 BTNL3 CD80 none CD33 BTNL3 CD86 none CD33 BTNL3 OX40none CD33 BTNL3 DAP10 none CD33 BTNL3 MyD88 none CD33 BTNL3 CD7 noneCD33 BTNL3 DAP12 none CD33 BTNL3 MyD88 none CD33 BTNL3 CD7 none CD33NKG2D CD28 none CD33 NKG2D CD8 none CD33 NKG2D CD4 none CD33 NKG2D b2cnone CD33 NKG2D CD137/41BB none CD33 NKG2D ICOS none CD33 NKG2D CD27none CD33 NKG2D CD28δ none CD33 NKG2D CD80 none CD33 NKG2D CD86 noneCD33 NKG2D OX40 none CD33 NKG2D DAP10 none CD33 NKG2D MyD88 none CD33NKG2D CD7 none CD33 NKG2D DAP12 none CD33 NKG2D MyD88 none CD33 NKG2DCD7 none

In some embodiments, the anti-CD33 binding agent is single chainvariable fragment (scFv) antibody. The affinity/specificity of ananti-CD33 scFv is driven in large part by specific sequences withincomplementarity determining regions (CDRs) in the heavy (V_(H)) andlight (V_(L)) chain. Each V_(H) and V_(L) sequence will have three CDRs(CDR1, CDR2, CDR3).

In some embodiments, the anti-CD33 binding agent is derived from naturalantibodies, such as monoclonal antibodies. In some cases, the antibodyis human. In some cases, the antibody has undergone an alteration torender it less immunogenic when administered to humans. For example, thealteration comprises one or more techniques selected from the groupconsisting of chimerization, humanization, CDR-grafting, deimmunization,and mutation of framework amino acids to correspond to the closest humangermline sequence.

Also disclosed are bi-specific CARs that target CD33 and at least oneadditional tumor antigen. Also disclosed are CARs designed to work onlyin conjunction with another CAR that binds a different antigen, such asa tumor antigen. For example, in these embodiments, the endodomain ofthe disclosed CAR can contain only an signaling domain (SD) or aco-stimulatory signaling region (CSR), but not both. The second CAR (orendogenous T-cell) provides the missing signal if it is activated. Forexample, if the disclosed CAR contains an SD but not a CSR, then theimmune effector cell containing this CAR is only activated if anotherCAR (or T-cell) containing a CSR binds its respective antigen. Likewise,if the disclosed CAR contains a CSR but not a SD, then the immuneeffector cell containing this CAR is only activated if another CAR (orT-cell) containing an SD binds its respective antigen.

Tumor antigens are proteins that are produced by tumor cells that elicitan immune response, particularly T-cell mediated immune responses. Theadditional antigen binding domain can be an antibody or a natural ligandof the tumor antigen. The selection of the additional antigen bindingdomain will depend on the particular type of cancer to be treated. Tumorantigens are well known in the art and include, for example, aglioma-associated antigen, carcinoembryonic antigen (CEA), EGFRvIII,IL-IIRa, IL-13Ra, EGFR, FAP, B7H3, Kit, CA LX, CS-1, MUC1, BCMA,bcr-abl, HER2, β-human chorionic gonadotropin, alphafetoprotein (AFP),ALK, CD19, CD123, cyclin BI, lectin-reactive AFP, Fos-related antigen 1,ADRB3, thyroglobulin, EphA2, RAGE-1, RUI, RU2, SSX2, AKAP-4, LCK,OY-TESI, PAX5, SART3, CLL-1, fucosyl GM1, GloboH, MN-CA IX, EPCAM,EVT6-AML, TGS5, human telomerase reverse transcriptase, plysialic acid,PLAC1, RUI, RU2 (AS), intestinal carboxyl esterase, lewisY, sLe, LY6K,mut hsp70-2, M-CSF, MYCN, RhoC, TRP-2, CYPIBI, BORIS, prostase,prostate-specific antigen (PSA), PAX3, PAP, NY-ESO-1, LAGE-la, LMP2,NCAM, p53, p53 mutant, Ras mutant, gplOO, prostein, OR51E2, PANX3, PSMA,PSCA, Her2/neu, hTERT, HMWMAA, HAVCR1, VEGFR2, PDGFR-beta, survivin andtelomerase, legumain, HPV E6, E7, sperm protein 17, SSEA-4, tyrosinase,TARP, VVT1, prostate-carcinoma tumor antigen-1 (PCTA-1), ML-IAP, MAGE,MAGE-A1, MAD-CT-1, MAD-CT-2, MelanA/MART 1, XAGE1, ELF2M, ERG (TMPRSS2ETS fusion gene), NA17, neutrophil elastase, sarcoma translocationbreakpoints, NY-BR-1, ephnnB2, CD20, CD22, CD24, CD30, TIM3, CD38,CD44v6, CD97, CD171, CD179a, androgen receptor, FAP, insulin growthfactor (IGF)-I, IGFII, IGF-I receptor, GD2, o-acetyl-GD2, GD3, GM3,GPRCSD, GPR20, CXORF61, folate receptor (FRa), folate receptor beta,ROR1, Flt3, TAG72, TN Ag, Tie 2, TEM1, TEM7R, CLDN6, TSHR, UPK2, andmesothelin. In a preferred embodiment, the tumor antigen is selectedfrom the group consisting of folate receptor (FRa), mesothelin,EGFRvIII, IL-13Ra, CD123, CD19, TIM3, BCMA, GD2, CLL-1, CA-IX, MUCI,HER2, and any combination thereof.

Non-limiting examples of tumor antigens include the following:Differentiation antigens such as tyrosinase, TRP-1, TRP-2 andtumor-specific multilineage antigens such as MAGE-1, MAGE-3, BAGE,GAGE-1, GAGE-2, pi 5; overexpressed embryonic antigens such as CEA;overexpressed oncogenes and mutated tumor-suppressor genes such as p53,Ras, HER-2/neu; unique tumor antigens resulting from chromosomaltranslocations; such as BCR-ABL, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR; andviral antigens, such as the Epstein Barr virus antigens EBVA and thehuman papillomavirus (HPV) antigens E6 and E7. Other large,protein-based antigens include TSP-180, MAGE-4, MAGE-5, MAGE-6, RAGE,NY-ESO, p185erbB2, p180erbB-3, c-met, nm-23H1, PSA, CA 19-9, CA 72-4,CAM 17.1, NuMa, K-ras, beta-Catenin, CDK4, Mum-1, p 15, p 16, 43-9F,5T4, 791Tgp72, alpha-fetoprotein, beta-HCG, BCA225, BTAA, CA 125, CA15-3\CA 27.29\BCAA, CA 195, CA 242, CA-50, CAM43, CD68\P1, CO-029,FGF-5, G250, Ga733\EpCAM, HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB/70K,NY-CO-1, RCASI, SDCCAG1 6, TA-90\Mac-2 binding protein\cyclophilmC-associated protein, TAAL6, TAG72, TLP, TPS, GPC3, MUC16, LMP1, EBMA-1,BARF-1, CS1, CD319, HER1, B7H6, L1CAM, IL6, and MET.

Nucleic Acids and Vectors

Also disclosed are polynucleotides and polynucleotide vectors encodingthe disclosed CD33-specific CARs that allow expression of theCD33-specific CARs in the disclosed immune effector cells.

Nucleic acid sequences encoding the disclosed CARs, and regions thereof,can be obtained using recombinant methods known in the art, such as, forexample by screening libraries from cells expressing the gene, byderiving the gene from a vector known to include the same, or byisolating directly from cells and tissues containing the same, usingstandard techniques. Alternatively, the gene of interest can be producedsynthetically, rather than cloned.

Expression of nucleic acids encoding CARs is typically achieved byoperably linking a nucleic acid encoding the CAR polypeptide to apromoter, and incorporating the construct into an expression vector.Typical cloning vectors contain transcription and translationterminators, initiation sequences, and promoters useful for regulationof the expression of the desired nucleic acid sequence.

The disclosed nucleic acid can be cloned into a number of types ofvectors. For example, the nucleic acid can be cloned into a vectorincluding, but not limited to a plasmid, a phagemid, a phage derivative,an animal virus, and a cosmid. Vectors of particular interest includeexpression vectors, replication vectors, probe generation vectors, andsequencing vectors.

Further, the expression vector may be provided to a cell in the form ofa viral vector. Viral vector technology is well known in the art and isdescribed, for example, in Sambrook et al. (2001, Molecular Cloning: ALaboratory Manual, Cold Spring Harbor Laboratory, New York), and inother virology and molecular biology manuals. Viruses, which are usefulas vectors include, but are not limited to, retroviruses, adenoviruses,adeno-associated viruses, herpes viruses, and lentiviruses. In general,a suitable vector contains an origin of replication functional in atleast one organism, a promoter sequence, convenient restrictionendonuclease sites, and one or more selectable markers. In someembodiments, the polynucleotide vectors are lentiviral or retroviralvectors.

A number of viral based systems have been developed for gene transferinto mammalian cells. For example, retroviruses provide a convenientplatform for gene delivery systems. A selected gene can be inserted intoa vector and packaged in retroviral particles using techniques known inthe art. The recombinant virus can then be isolated and delivered tocells of the subject either in vivo or ex vivo.

One example of a suitable promoter is the immediate earlycytomegalovirus (CMV) promoter sequence. This promoter sequence is astrong constitutive promoter sequence capable of driving high levels ofexpression of any polynucleotide sequence operatively linked thereto.Another example of a suitable promoter is Elongation Growth Factor-1α(EF-1α). However, other constitutive promoter sequences may also beused, including, but not limited to the simian virus 40 (SV40) earlypromoter, MND (myeloproliferative sarcoma virus) promoter, mouse mammarytumor virus (MMTV), human immunodeficiency virus (HIV) long terminalrepeat (LTR) promoter, MoMuLV promoter, an avian leukemia viruspromoter, an Epstein-Barr virus immediate early promoter, a Rous sarcomavirus promoter, as well as human gene promoters such as, but not limitedto, the actin promoter, the myosin promoter, the hemoglobin promoter,and the creatine kinase promoter. The promoter can alternatively be aninducible promoter. Examples of inducible promoters include, but are notlimited to a metallothionine promoter, a glucocorticoid promoter, aprogesterone promoter, and a tetracycline promoter.

Additional promoter elements, e.g., enhancers, regulate the frequency oftranscriptional initiation. Typically, these are located in the region30-110 bp upstream of the start site, although a number of promotershave recently been shown to contain functional elements downstream ofthe start site as well. The spacing between promoter elements frequentlyis flexible, so that promoter function is preserved when elements areinverted or moved relative to one another.

In order to assess the expression of a CAR polypeptide or portionsthereof, the expression vector to be introduced into a cell can alsocontain either a selectable marker gene or a reporter gene or both tofacilitate identification and selection of expressing cells from thepopulation of cells sought to be transfected or infected through viralvectors. In other aspects, the selectable marker may be carried on aseparate piece of DNA and used in a co-transfection procedure. Bothselectable markers and reporter genes may be flanked with appropriateregulatory sequences to enable expression in the host cells. Usefulselectable markers include, for example, antibiotic-resistance genes.

Reporter genes are used for identifying potentially transfected cellsand for evaluating the functionality of regulatory sequences. Ingeneral, a reporter gene is a gene that is not present in or expressedby the recipient organism or tissue and that encodes a polypeptide whoseexpression is manifested by some easily detectable property, e.g.,enzymatic activity. Expression of the reporter gene is assayed at asuitable time after the DNA has been introduced into the recipientcells. Suitable reporter genes may include genes encoding luciferase,beta-galactosidase, chloramphenicol acetyl transferase, secretedalkaline phosphatase, or the green fluorescent protein gene. Suitableexpression systems are well known and may be prepared using knowntechniques or obtained commercially. In general, the construct with theminimal 5′ flanking region showing the highest level of expression ofreporter gene is identified as the promoter. Such promoter regions maybe linked to a reporter gene and used to evaluate agents for the abilityto modulate promoter-driven transcription.

Methods of introducing and expressing genes into a cell are known in theart. In the context of an expression vector, the vector can be readilyintroduced into a host cell, e.g., mammalian, bacterial, yeast, orinsect cell by any method in the art. For example, the expression vectorcan be transferred into a host cell by physical, chemical, or biologicalmeans.

Physical methods for introducing a polynucleotide into a host cellinclude calcium phosphate precipitation, lipofection, particlebombardment, microinjection, electroporation, and the like. Methods forproducing cells comprising vectors and/or exogenous nucleic acids arewell-known in the art. See, for example, Sambrook et al. (2001,Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory,New York).

Biological methods for introducing a polynucleotide of interest into ahost cell include the use of DNA and RNA vectors. Viral vectors, andespecially retroviral vectors, have become the most widely used methodfor inserting genes into mammalian, e.g., human cells.

Chemical means for introducing a polynucleotide into a host cell includecolloidal dispersion systems, such as macromolecule complexes,nanocapsules, microspheres, beads, and lipid-based systems includingoil-in-water emulsions, micelles, mixed micelles, and liposomes. Anexemplary colloidal system for use as a delivery vehicle in vitro and invivo is a liposome (e.g., an artificial membrane vesicle).

In the case where a non-viral delivery system is utilized, an exemplarydelivery vehicle is a liposome. In another aspect, the nucleic acid maybe associated with a lipid. The nucleic acid associated with a lipid maybe encapsulated in the aqueous interior of a liposome, interspersedwithin the lipid bilayer of a liposome, attached to a liposome via alinking molecule that is associated with both the liposome and theoligonucleotide, entrapped in a liposome, complexed with a liposome,dispersed in a solution containing a lipid, mixed with a lipid, combinedwith a lipid, contained as a suspension in a lipid, contained orcomplexed with a micelle, or otherwise associated with a lipid. Lipid,lipid/DNA or lipid/expression vector associated compositions are notlimited to any particular structure in solution. For example, they maybe present in a bilayer structure, as micelles, or with a “collapsed”structure. They may also simply be interspersed in a solution, possiblyforming aggregates that are not uniform in size or shape. Lipids arefatty substances which may be naturally occurring or synthetic lipids.For example, lipids include the fatty droplets that naturally occur inthe cytoplasm as well as the class of compounds which contain long-chainaliphatic hydrocarbons and their derivatives, such as fatty acids,alcohols, amines, amino alcohols, and aldehydes. Lipids suitable for usecan be obtained from commercial sources. For example, dimyristylphosphatidylcholine (“DMPC”) can be obtained from Sigma, St. Louis, Mo.;dicetyl phosphate (“DCP”) can be obtained from K & K Laboratories(Plainview, N.Y.); cholesterol (“Choi”) can be obtained fromCalbiochem-Behring; dimyristyl phosphatidylglycerol (“DMPG”) and otherlipids may be obtained from Avanti Polar Lipids, Inc, (Birmingham,Ala.).

Immune Effector Cells

Also disclosed are immune effector cells that are engineered to expressthe disclosed CARs (also referred to herein as “CAR-T cells.” Thesecells are preferably obtained from the subject to be treated (i.e. areautologous). However, in some embodiments, immune effector cell lines ordonor effector cells (allogeneic) are used.

Immune effector cells can be obtained from a number of sources,including peripheral blood mononuclear cells, bone marrow, lymph nodetissue, cord blood, thymus tissue, tissue from a site of infection,ascites, pleural effusion, spleen tissue, and tumors. Immune effectorcells can be obtained from blood collected from a subject using anynumber of techniques known to the skilled artisan, such as Ficoll™separation. For example, cells from the circulating blood of anindividual may be obtained by apheresis. In some embodiments, immuneeffector cells are isolated from peripheral blood lymphocytes by lysingthe red blood cells and depleting the monocytes, for example, bycentrifugation through a PERCOLL™ gradient or by counterflow centrifugalelutriation. A specific subpopulation of immune effector cells can befurther isolated by positive or negative selection techniques. Forexample, immune effector cells can be isolated using a combination ofantibodies directed to surface markers unique to the positively selectedcells, e.g., by incubation with antibody-conjugated beads for a timeperiod sufficient for positive selection of the desired immune effectorcells. Alternatively, enrichment of immune effector cells population canbe accomplished by negative selection using a combination of antibodiesdirected to surface markers unique to the negatively selected cells.

In some embodiments, the immune effector cells comprise any leukocyteinvolved in defending the body against infectious disease and foreignmaterials. For example, the immune effector cells can compriselymphocytes, monocytes, macrophages, dentritic cells, mast cells,neutrophils, basophils, eosinophils, or any combinations thereof. Forexample, the immune effector cells can comprise T lymphocytes.

T cells or T lymphocytes can be distinguished from other lymphocytes,such as B cells and natural killer cells (NK cells), by the presence ofa T-cell receptor (TCR) on the cell surface. They are called T cellsbecause they mature in the thymus (although some also mature in thetonsils). There are several subsets of T cells, each with a distinctfunction.

T helper cells (T_(H) cells) assist other white blood cells inimmunologic processes, including maturation of B cells into plasma cellsand memory B cells, and activation of cytotoxic T cells and macrophages.These cells are also known as CD4+ T cells because they express the CD4glycoprotein on their surface. Helper T cells become activated when theyare presented with peptide antigens by MHC class II molecules, which areexpressed on the surface of antigen-presenting cells (APCs). Onceactivated, they divide rapidly and secrete small proteins calledcytokines that regulate or assist in the active immune response. Thesecells can differentiate into one of several subtypes, including T_(H)1,T_(H)2, T_(H)3, T_(H)17, T_(H)9, or T_(FH), which secrete differentcytokines to facilitate a different type of immune response.

Cytotoxic T cells (T_(C) cells, or CTLs) destroy virally infected cellsand tumor cells, and are also implicated in transplant rejection. Thesecells are also known as CD8⁺ T cells since they express the CD8glycoprotein at their surface. These cells recognize their targets bybinding to antigen associated with MHC class I molecules, which arepresent on the surface of all nucleated cells. Through IL-10, adenosineand other molecules secreted by regulatory T cells, the CD8+ cells canbe inactivated to an anergic state, which prevents autoimmune diseases.

Memory T cells are a subset of antigen-specific T cells that persistlong-term after an infection has resolved. They quickly expand to largenumbers of effector T cells upon re-exposure to their cognate antigen,thus providing the immune system with “memory” against past infections.Memory cells may be either CD4⁺ or CD8⁺. Memory T cells typicallyexpress the cell surface protein CD45RO.

Regulatory T cells (T_(reg) cells), formerly known as suppressor Tcells, are crucial for the maintenance of immunological tolerance. Theirmajor role is to shut down T cell-mediated immunity toward the end of animmune reaction and to suppress auto-reactive T cells that escaped theprocess of negative selection in the thymus. Two major classes of CD4⁺T_(reg) cells have been described—naturally occurring T_(reg) cells andadaptive T_(reg) cells.

Natural killer T (NKT) cells (not to be confused with natural killer(NK) cells) bridge the adaptive immune system with the innate immunesystem. Unlike conventional T cells that recognize peptide antigenspresented by major histocompatibility complex (MHC) molecules, NKT cellsrecognize glycolipid antigen presented by a molecule called CD1d.

In some embodiments, the T cells comprise a mixture of CD4+ cells. Inother embodiments, the T cells are enriched for one or more subsetsbased on cell surface expression. For example, in some cases, the Tcomprise are cytotoxic CD8⁺ T lymphocytes. In some embodiments, the Tcells comprise γδ T cells, which possess a distinct T-cell receptor(TCR) having one γ chain and one δ chain instead of α and β chains.

Natural-killer (NK) cells are CD56⁺CD3⁻ large granular lymphocytes thatcan kill virally infected and transformed cells, and constitute acritical cellular subset of the innate immune system (Godfrey J, et al.Leuk Lymphoma 2012 53:1666-1676). Unlike cytotoxic CD8⁺ T lymphocytes,NK cells launch cytotoxicity against tumor cells without the requirementfor prior sensitization, and can also eradicate MHC-I-negative cells(Narni-Mancinelli E, et al. Int Immunol 2011 23:427-431). NK cells aresafer effector cells, as they may avoid the potentially lethalcomplications of cytokine storms (Morgan R A, et al. Mol Ther 201018:843-851), tumor lysis syndrome (Porter D L, et al. N Engl J Med 2011365:725-733), and on-target, off-tumor effects. Although NK cells have awell-known role as killers of cancer cells, and NK cell impairment hasbeen extensively documented as crucial for progression of MM (Godfrey J,et al. Leuk Lymphoma 2012 53:1666-1676; Fauriat C, et al. Leukemia 200620:732-733), the means by which one might enhance NK cell-mediatedanti-MM activity has been largely unexplored prior to the disclosedCARs.

Therapeutic Methods

Immune effector cells expressing the disclosed CARs can elicit ananti-tumor immune response against CD33-expressing cancer cells. Theanti-tumor immune response elicited by the disclosed CAR-modified immuneeffector cells may be an active or a passive immune response. Inaddition, the CAR-mediated immune response may be part of an adoptiveimmunotherapy approach in which CAR-modified immune effector cellsinduce an immune response specific to CD33.

Adoptive transfer of immune effector cells expressing chimeric antigenreceptors is a promising anti-cancer therapeutic. Following thecollection of a patient's immune effector cells, the cells may begenetically engineered to express the disclosed CD33-specific CARs, theninfused back into the patient.

The disclosed CAR-modified immune effector cells may be administeredeither alone, or as a pharmaceutical composition in combination withdiluents and/or with other components such as IL-2, IL-15, or othercytokines or cell populations. Briefly, pharmaceutical compositions maycomprise a target cell population as described herein, in combinationwith one or more pharmaceutically or physiologically acceptablecarriers, diluents or excipients. Such compositions may comprise bufferssuch as neutral buffered saline, phosphate buffered saline and the like;carbohydrates such as glucose, mannose, sucrose or dextrans, mannitol;proteins; polypeptides or amino acids such as glycine; antioxidants;chelating agents such as EDTA or glutathione; adjuvants (e.g., aluminumhydroxide); and preservatives. Compositions for use in the disclosedmethods are in some embodiments formulated for intravenousadministration. Pharmaceutical compositions may be administered in anymanner appropriate treat MM. The quantity and frequency ofadministration will be determined by such factors as the condition ofthe patient, and the severity of the patient's disease, althoughappropriate dosages may be determined by clinical trials.

When “an immunologically effective amount”, “an anti-tumor effectiveamount”, “an tumor-inhibiting effective amount”, or “therapeutic amount”is indicated, the precise amount of the compositions of the presentinvention to be administered can be determined by a physician withconsideration of individual differences in age, weight, tumor size,extent of infection or metastasis, and condition of the patient(subject). It can generally be stated that a pharmaceutical compositioncomprising the T cells described herein may be administered at a dosageof 10⁴ to 10⁹ cells/kg body weight, such as 10⁵ to 10⁶ cells/kg bodyweight, including all integer values within those ranges. T cellcompositions may also be administered multiple times at these dosages.The cells can be administered by using infusion techniques that arecommonly known in immunotherapy (see, e.g., Rosenberg et al., New Eng.J. of Med. 319:1676, 1988). The optimal dosage and treatment regime fora particular patient can readily be determined by one skilled in the artof medicine by monitoring the patient for signs of disease and adjustingthe treatment accordingly.

In certain embodiments, it may be desired to administer activated Tcells to a subject and then subsequently re-draw blood (or have anapheresis performed), activate T cells therefrom according to thedisclosed methods, and reinfuse the patient with these activated andexpanded T cells. This process can be carried out multiple times everyfew weeks. In certain embodiments, T cells can be activated from blooddraws of from 10 cc to 400 cc. In certain embodiments, T cells areactivated from blood draws of 20 cc, 30 cc, 40 cc, 50 cc, 60 cc, 70 cc,80 cc, 90 cc, or 100 cc. Using this multiple blood draw/multiplereinfusion protocol may serve to select out certain populations of Tcells.

The administration of the disclosed compositions may be carried out inany convenient manner, including by injection, transfusion, orimplantation. The compositions described herein may be administered to apatient subcutaneously, intradermally, intratumorally, intranodally,intramedullary, intramuscularly, by intravenous (i.v.) injection, orintraperitoneally. In some embodiments, the disclosed compositions areadministered to a patient by intradermal or subcutaneous injection. Insome embodiments, the disclosed compositions are administered by i.v.injection. The compositions may also be injected directly into a tumor,lymph node, or site of infection.

In certain embodiments, the disclosed CAR-modified immune effector cellsare administered to a patient in conjunction with (e.g., before,simultaneously or following) any number of relevant treatmentmodalities, including but not limited to thalidomide, dexamethasone,bortezomib, and lenalidomide. In further embodiments, the CAR-modifiedimmune effector cells may be used in combination with chemotherapy,radiation, immunosuppressive agents, such as cyclosporin, azathioprine,methotrexate, mycophenolate, and FK506, antibodies, or otherimmunoablative agents such as CAM PATH, anti-CD3 antibodies or otherantibody therapies, cytoxin, fludaribine, cyclosporin, FK506, rapamycin,mycophenolic acid, steroids, FR901228, cytokines, and irradiation. Insome embodiments, the CAR-modified immune effector cells areadministered to a patient in conjunction with (e.g., before,simultaneously or following) bone marrow transplantation, T cellablative therapy using either chemotherapy agents such as, fludarabine,external-beam radiation therapy (XRT), cyclophosphamide, or antibodiessuch as OKT3 or CAMPATH. In another embodiment, the cell compositions ofthe present invention are administered following B-cell ablative therapysuch as agents that react with CD20, e.g., Rituxan. For example, in someembodiments, subjects may undergo standard treatment with high dosechemotherapy followed by peripheral blood stem cell transplantation. Incertain embodiments, following the transplant, subjects receive aninfusion of the expanded immune cells of the present invention. In anadditional embodiment, expanded cells are administered before orfollowing surgery.

The cancer of the disclosed methods can be any CD33-expressing cell in asubject undergoing unregulated growth, invasion, or metastasis. Cancersthat express CD33 include prostate cancer, ovarian cancer,adenocarcinoma of the lung, breast cancer, endometrial cancer, gastriccancer, colon cancer, and pancreatic cancer. CD33 has also been found onJurkat cells. In some aspects, the cancer is a gallbladder cancer,exocrine adenocarcinoma, or apocrine adenocarcinomas. In some cases, thecancer comprises myelodysplastic syndrome, acute myeloid leukemia, orbi-phenotypic leukemia.

In some aspects, the cancer can be any neoplasm or tumor for whichradiotherapy is currently used. Alternatively, the cancer can be aneoplasm or tumor that is not sufficiently sensitive to radiotherapyusing standard methods. Thus, the cancer can be a sarcoma, lymphoma,leukemia, carcinoma, blastoma, or germ cell tumor. A representative butnon-limiting list of cancers that the disclosed compositions can be usedto treat include lymphoma, B cell lymphoma, T cell lymphoma, mycosisfungoides, Hodgkin's Disease, myeloid leukemia, bladder cancer, braincancer, nervous system cancer, head and neck cancer, squamous cellcarcinoma of head and neck, kidney cancer, lung cancers such as smallcell lung cancer and non-small cell lung cancer,neuroblastoma/glioblastoma, ovarian cancer, pancreatic cancer, prostatecancer, skin cancer, liver cancer, melanoma, squamous cell carcinomas ofthe mouth, throat, larynx, and lung, endometrial cancer, cervicalcancer, cervical carcinoma, breast cancer, epithelial cancer, renalcancer, genitourinary cancer, pulmonary cancer, esophageal carcinoma,head and neck carcinoma, large bowel cancer, hematopoietic cancers;testicular cancer; colon and rectal cancers, prostatic cancer, andpancreatic cancer.

The disclosed CARs can be used in combination with any compound, moietyor group which has a cytotoxic or cytostatic effect. Drug moietiesinclude chemotherapeutic agents, which may function as microtubulininhibitors, mitosis inhibitors, topoisomerase inhibitors, or DNAintercalators, and particularly those which are used for cancer therapy.

The disclosed CARs can be used in combination with a checkpointinhibitor. The two known inhibitory checkpoint pathways involvesignaling through the cytotoxic T-lymphocyte antigen-4 (CTLA-4) andprogrammed-death 1 (PD-1) receptors. These proteins are members of theCD28-B7 family of cosignaling molecules that play important rolesthroughout all stages of T cell function. The PD-1 receptor (also knownas CD279) is expressed on the surface of activated T cells. Its ligands,PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273), are expressed on thesurface of APCs such as dendritic cells or macrophages. PD-L1 is thepredominant ligand, while PD-L2 has a much more restricted expressionpattern. When the ligands bind to PD-1, an inhibitory signal istransmitted into the T cell, which reduces cytokine production andsuppresses T-cell proliferation. Checkpoint inhibitors include, but arenot limited to antibodies that block PD-1 (Nivolumab (BMS-936558 orMDX1106), CT-011, MK-3475), PD-L1 (MDX-1105 (BMS-936559), MPDL3280A,MSB0010718C), PD-L2 (rHIgM12B7), CTLA-4 (Ipilimumab (MDX-010),Tremelimumab (CP-675,206)), IDO, B7-H3 (MGA271), B7-H4, TIM3, LAG-3(BMS-986016).

Human monoclonal antibodies to programmed death 1 (PD-1) and methods fortreating cancer using anti-PD-1 antibodies alone or in combination withother immunotherapeutics are described in U.S. Pat. No. 8,008,449, whichis incorporated by reference for these antibodies. Anti-PD-L1 antibodiesand uses therefor are described in U.S. Pat. No. 8,552,154, which isincorporated by reference for these antibodies. Anticancer agentcomprising anti-PD-1 antibody or anti-PD-L1 antibody are described inU.S. Pat. No. 8,617,546, which is incorporated by reference for theseantibodies.

In some embodiments, the PDL1 inhibitor comprises an antibody thatspecifically binds PDL1, such as BMS-936559 (Bristol-Myers Squibb) orMPDL3280A (Roche). In some embodiments, the PD1 inhibitor comprises anantibody that specifically binds PD1, such as lambrolizumab (Merck),nivolumab (Bristol-Myers Squibb), or MEDI4736 (AstraZeneca). Humanmonoclonal antibodies to PD-1 and methods for treating cancer usinganti-PD-1 antibodies alone or in combination with otherimmunotherapeutics are described in U.S. Pat. No. 8,008,449, which isincorporated by reference for these antibodies. Anti-PD-L1 antibodiesand uses therefor are described in U.S. Pat. No. 8,552,154, which isincorporated by reference for these antibodies. Anticancer agentcomprising anti-PD-1 antibody or anti-PD-L1 antibody are described inU.S. Pat. No. 8,617,546, which is incorporated by reference for theseantibodies.

The disclosed CARs can be used in combination with other cancerimmunotherapies. There are two distinct types of immunotherapy: passiveimmunotherapy uses components of the immune system to direct targetedcytotoxic activity against cancer cells, without necessarily initiatingan immune response in the patient, while active immunotherapy activelytriggers an endogenous immune response. Passive strategies include theuse of the monoclonal antibodies (mAbs) produced by B cells in responseto a specific antigen. The development of hybridoma technology in the1970s and the identification of tumor-specific antigens permitted thepharmaceutical development of mAbs that could specifically target tumorcells for destruction by the immune system. Thus far, mAbs have been thebiggest success story for immunotherapy; the top three best-sellinganticancer drugs in 2012 were mAbs. Among them is rituximab (Rituxan,Genentech), which binds to the CD20 protein that is highly expressed onthe surface of B cell malignancies such as non-Hodgkin's lymphoma (NHL).Rituximab is approved by the FDA for the treatment of NHL and chroniclymphocytic leukemia (CLL) in combination with chemotherapy. Anotherimportant mAb is trastuzumab (Herceptin; Genentech), whichrevolutionized the treatment of HER2 (human epidermal growth factorreceptor 2)-positive breast cancer by targeting the expression of HER2.

Generating optimal “killer” CD8 T cell responses also requires T cellreceptor activation plus co-stimulation, which can be provided throughligation of tumor necrosis factor receptor family members, includingOX40 (CD134) and 4-1BB (CD137). OX40 is of particular interest astreatment with an activating (agonist) anti-OX40 mAb augments T celldifferentiation and cytolytic function leading to enhanced anti-tumorimmunity against a variety of tumors.

In some embodiments, such an additional therapeutic agent may beselected from an antimetabolite, such as methotrexate, 6-mercaptopurine,6-thioguanine, cytarabine, fludarabine, 5-fluorouracil, decarbazine,hydroxyurea, asparaginase, gemcitabine or cladribine.

In some embodiments, such an additional therapeutic agent may beselected from an alkylating agent, such as mechlorethamine, thioepa,chlorambucil, melphalan, carmustine (BSNU), lomustine (CCNU),cyclophosphamide, busulfan, dibromomannitol, streptozotocin, dacarbazine(DTIC), procarbazine, mitomycin C, cisplatin and other platinumderivatives, such as carboplatin.

In some embodiments, such an additional therapeutic agent is a targetedagent, such as ibrutinib or idelalisib.

In some embodiments, such an additional therapeutic agent is anepigenetic modifier such as azacitdine or vidaza.

In some embodiments, such an additional therapeutic agent may beselected from an anti-mitotic agent, such as taxanes, for instancedocetaxel, and paclitaxel, and vinca alkaloids, for instance vindesine,vincristine, vinblastine, and vinorelbine.

In some embodiments, such an additional therapeutic agent may beselected from a topoisomerase inhibitor, such as topotecan oririnotecan, or a cytostatic drug, such as etoposide and teniposide.

In some embodiments, such an additional therapeutic agent may beselected from a growth factor inhibitor, such as an inhibitor of ErbBl(EGFR) (such as an EGFR antibody, e.g. zalutumumab, cetuximab,panitumumab or nimotuzumab or other EGFR inhibitors, such as gefitinibor erlotinib), another inhibitor of ErbB2 (HER2/neu) (such as a HER2antibody, e.g. trastuzumab, trastuzumab-DM I or pertuzumab) or aninhibitor of both EGFR and HER2, such as lapatinib).

In some embodiments, such an additional therapeutic agent may beselected from a tyrosine kinase inhibitor, such as imatinib (Glivec,Gleevec ST1571) or lapatinib.

Therefore, in some embodiments, a disclosed antibody is used incombination with ofatumumab, zanolimumab, daratumumab, ranibizumab,nimotuzumab, panitumumab, hu806, daclizumab (Zenapax), basiliximab(Simulect), infliximab (Remicade), adalimumab (Humira), natalizumab(Tysabri), omalizumab (Xolair), efalizumab (Raptiva), and/or rituximab.

In some embodiments, a therapeutic agent for use in combination with aCARs for treating the disorders as described above may be an anti-cancercytokine, chemokine, or combination thereof. Examples of suitablecytokines and growth factors include IFNγ, IL-2, IL-4, IL-6, IL-7,IL-10, IL-12, IL-13, IL-15, IL-18, IL-23, IL-24, IL-27, IL-28a, IL-28b,IL-29, KGF, IFNa (e.g., INFa2b), IFN, GM-CSF, CD40L, Flt3 ligand, stemcell factor, ancestim, and TNFa. Suitable chemokines may includeGlu-Leu-Arg (ELR)-negative chemokines such as IP-10, MCP-3, MIG, andSDF-la from the human CXC and C—C chemokine families. Suitable cytokinesinclude cytokine derivatives, cytokine variants, cytokine fragments, andcytokine fusion proteins.

In some embodiments, a therapeutic agent for use in combination with aCARs for treating the disorders as described above may be a cell cyclecontrol/apoptosis regulator (or “regulating agent”). A cell cyclecontrol/apoptosis regulator may include molecules that target andmodulate cell cycle control/apoptosis regulators such as (i) cdc-25(such as NSC 663284), (ii) cyclin-dependent kinases that overstimulatethe cell cycle (such as flavopiridol (L868275, HMR1275),7-hydroxystaurosporine (UCN-01, KW-2401), and roscovitine(R-roscovitine, CYC202)), and (iii) telomerase modulators (such asBIBR1532, SOT-095, GRN163 and compositions described in for instanceU.S. Pat. Nos. 6,440,735 and 6,713,055). Non-limiting examples ofmolecules that interfere with apoptotic pathways include TNF-relatedapoptosis-inducing ligand (TRAIL)/apoptosis-2 ligand (Apo-2L),antibodies that activate TRAIL receptors, IFNs, and anti-sense Bcl-2.

In some embodiments, a therapeutic agent for use in combination with aCARs for treating the disorders as described above may be a hormonalregulating agent, such as agents useful for anti-androgen andanti-estrogen therapy. Examples of such hormonal regulating agents aretamoxifen, idoxifene, fulvestrant, droloxifene, toremifene, raloxifene,diethylstilbestrol, ethinyl estradiol/estinyl, an antiandrogene (such asflutaminde/eulexin), a progestin (such as such as hydroxyprogesteronecaproate, medroxy-progesterone/provera, megestrol acepate/megace), anadrenocorticosteroid (such as hydrocortisone, prednisone), luteinizinghormone-releasing hormone (and analogs thereof and other LHRH agonistssuch as buserelin and goserelin), an aromatase inhibitor (such asanastrazole/arimidex, aminoglutethimide/cytraden, exemestane) or ahormone inhibitor (such as octreotide/sandostatin).

In some embodiments, a therapeutic agent for use in combination with anCARs for treating the disorders as described above may be an anti-cancernucleic acid or an anti-cancer inhibitory RNA molecule.

Combined administration, as described above, may be simultaneous,separate, or sequential. For simultaneous administration the agents maybe administered as one composition or as separate compositions, asappropriate.

In some embodiments, the disclosed CARs is administered in combinationwith radiotherapy. Radiotherapy may comprise radiation or associatedadministration of radiopharmaceuticals to a patient is provided. Thesource of radiation may be either external or internal to the patientbeing treated (radiation treatment may, for example, be in the form ofexternal beam radiation therapy (EBRT) or brachytherapy (BT)).Radioactive elements that may be used in practicing such methodsinclude, e.g., radium, cesium-137, iridium-192, americium-241, gold-198,cobalt-57, copper-67, technetium-99, iodide-123, iodide-131, andindium-111.

In some embodiments, the disclosed CARs is administered in combinationwith surgery.

CAR-T cells may be designed in several ways that enhance tumorcytotoxicity and specificity, evade tumor immunosuppression, avoid hostrejection, and prolong their therapeutic half-life. TRUCK (T-cellsRedirected for Universal Cytokine Killing) T cells for example, possessa CAR but are also engineered to release cytokines such as IL-12 thatpromote tumor killing. Because these cells are designed to release amolecular payload upon activation of the CAR once localized to the tumorenvironment, these CAR-T cells are sometimes also referred to as‘armored CARs’. Several cytokines as cancer therapies are beinginvestigated both pre-clinically and clinically, and may also proveuseful when similarly incorporated into a TRUCK form of CAR-T therapy.Among these include IL-2, IL-3. IL-4, IL-5, IL-6, IL-7, IL-10, IL-12,IL-13, IL-15, IL-18, M-CSF, GM-CSF, IFN-α, IFN-γ, TNF-α, TRAIL, FLT3ligand, Lymphotactin, and TGF-β (Dranoff 2004). “Self-driving” or“homing” CAR-T cells are engineered to express a chemokine receptor inaddition to their CAR. As certain chemokines can be upregulated intumors, incorporation of a chemokine receptor aids in tumor traffickingto and infiltration by the adoptive T-cell, thereby enhancing bothspecificity and functionality of the CAR-T (Moon 2011). Universal CAR-Tcells also possess a CAR, but are engineered such that they do notexpress endogenous TCR (T-cell receptor) or MHC (majorhistocompatibility complex) proteins. Removal of these two proteins fromthe signaling repertoire of the adoptive T-cell therapy preventsgraft-versus-host-disease and rejection, respectively. Armored CAR-Tcells are additionally so named for their ability to evade tumorimmunosuppression and tumor-induced CAR-T hypofunction. These particularCAR-Ts possess a CAR, and may be engineered to not express checkpointinhibitors. Alternatively, these CAR-Ts can be co-administered with amonoclonal antibody (mAb) that blocks checkpoint signaling.Administration of an anti-PDL1 antibody significantly restored thekilling ability of CAR TILs (tumor infiltrating lymphocytes). WhilePD1-PDL1 and CTLA-4-CD80/CD86 signaling pathways have been investigated,it is possible to target other immune checkpoint signaling molecules inthe design of an armored CAR-T including LAG-3, Tim-3, IDO-1, 2B4, andKIR. Other intracellular inhibitors of TILs include phosphatases (SHP1),ubiquitin-ligases (i.e., cbl-b), and kinases (i.e., diacylglycerolkinase). Armored CAR-Ts may also be engineered to express proteins orreceptors that protect them against or make them resistant to theeffects of tumor-secreted cytokines. For example, CTLs (cytotoxic Tlymphocytes) transduced with the double negative form of the TGF-βreceptor are resistant to the immunosuppression by lymphoma secretedTGF-β. These transduced cells showed notably increased antitumoractivity in vivo when compared to their control counterparts.

Tandem and dual CAR-T cells are unique in that they possess two distinctantigen binding domains. A tandem CAR contains two sequential antigenbinding domains facing the extracellular environment connected to theintracellular costimulatory and stimulatory domains. A dual CAR isengineered such that one extracellular antigen binding domain isconnected to the intracellular costimulatory domain and a second,distinct extracellular antigen binding domain is connected to theintracellular stimulatory domain. Because the stimulatory andcostimulatory domains are split between two separate antigen bindingdomains, dual CARs are also referred to as “split CARs”. In both tandemand dual CAR designs, binding of both antigen binding domains isnecessary to allow signaling of the CAR circuit in the T-cell. Becausethese two CAR designs have binding affinities for different, distinctantigens, they are also referred to as “bi-specific” CARs.

One primary concern with CAR-T cells as a form of “living therapeutic”is their manipulability in vivo and their potential immune-stimulatingside effects. To better control CAR-T therapy and prevent againstunwanted side effects, a variety of features have been engineeredincluding off-switches, safety mechanisms, and conditional controlmechanisms. Both self-destruct and marked/tagged CAR-T cells forexample, are engineered to have an “off-switch” that promotes clearanceof the CAR-expressing T-cell. A self-destruct CAR-T contains a CAR, butis also engineered to express a pro-apoptotic suicide gene or“elimination gene” inducible upon administration of an exogenousmolecule. A variety of suicide genes may be employed for this purpose,including HSV-TK (herpes simplex virus thymidine kinase), Fas, iCasp9(inducible caspase 9), CD20, MYC TAG, and truncated EGFR (endothelialgrowth factor receptor). HSK for example, will convert the prodrugganciclovir (GCV) into GCV-triphosphate that incorporates itself intoreplicating DNA, ultimately leading to cell death. iCasp9 is a chimericprotein containing components of FK506-binding protein that binds thesmall molecule AP1903, leading to caspase 9 dimerization and apoptosis.A marked/tagged CAR-T cell however, is one that possesses a CAR but alsois engineered to express a selection marker. Administration of a mAbagainst this selection marker will promote clearance of the CAR-T cell.Truncated EGFR is one such targetable antigen by the anti-EGFR mAb, andadministration of cetuximab works to promotes elimination of the CAR-Tcell. CARs created to have these features are also referred to as sCARsfor ‘switchable CARs’, and RCARs for ‘regulatable CARs’. A “safety CAR”,also known as an “inhibitory CAR” (iCAR), is engineered to express twoantigen binding domains. One of these extracellular domains is directedagainst a tumor related antigen and bound to an intracellularcostimulatory and stimulatory domain. The second extracellular antigenbinding domain however is specific for normal tissue and bound to anintracellular checkpoint domain such as CTLA4, PD1, or CD45.Incorporation of multiple intracellular inhibitory domains to the iCARis also possible. Some inhibitory molecules that may provide theseinhibitory domains include B7-H1, B7-1, CD160, PIH, 2B4, CEACAM(CEACAM-1. CEACAM-3, and/or CEACAM-5), LAG-3, TIGIT, BTLA, LAIR1, andTGFβ-R. In the presence of normal tissue, stimulation of this secondantigen binding domain will work to inhibit the CAR. It should be notedthat due to this dual antigen specificity, iCARs are also a form ofbi-specific CAR-T cells. The safety CAR-T engineering enhancesspecificity of the CAR-T cell for tumor tissue, and is advantageous insituations where certain normal tissues may express very low levels of atumor associated antigen that would lead to off target effects with astandard CAR (Morgan 2010). A conditional CAR-T cell expresses anextracellular antigen binding domain connected to an intracellularcostimulatory domain and a separate, intracellular costimulator. Thecostimulatory and stimulatory domain sequences are engineered in such away that upon administration of an exogenous molecule the resultantproteins will come together intracellularly to complete the CAR circuit.In this way, CAR-T activation can be modulated, and possibly even‘fine-tuned’ or personalized to a specific patient. Similar to a dualCAR design, the stimulatory and costimulatory domains are physicallyseparated when inactive in the conditional CAR; for this reason thesetoo are also referred to as a “split CAR”.

In some embodiments, two or more of these engineered features may becombined to create an enhanced, multifunctional CAR-T. For example, itis possible to create a CAR-T cell with either dual- or conditional-CARdesign that also releases cytokines like a TRUCK. In some embodiments, adual-conditional CAR-T cell could be made such that it expresses twoCARs with two separate antigen binding domains against two distinctcancer antigens, each bound to their respective costimulatory domains.The costimulatory domain would only become functional with thestimulatory domain after the activating molecule is administered. Forthis CAR-T cell to be effective the cancer must express both cancerantigens and the activating molecule must be administered to thepatient; this design thereby incorporating features of both dual andconditional CAR-T cells.

Typically, CAR-T cells are created using α-β T cells, however γ-δ Tcells may also be used. In some embodiments, the described CARconstructs, domains, and engineered features used to generate CAR-Tcells could similarly be employed in the generation of other types ofCAR-expressing immune cells including NK (natural killer) cells, Bcells, mast cells, myeloid-derived phagocytes, and NKT cells.Alternatively, a CAR-expressing cell may be created to have propertiesof both T-cell and NK cells. In an additional embodiment, the transducedwith CARs may be autologous or allogeneic.

Several different methods for CAR expression may be used includingretroviral transduction (including γ-retroviral), lentiviraltransduction, transposon/transposases (Sleeping Beauty and PiggyBacsystems), and messenger RNA transfer-mediated gene expression. Geneediting (gene insertion or gene deletion/disruption) has become ofincreasing importance with respect to the possibility for engineeringCAR-T cells as well. CRISPR-Cas9, ZFN (zinc finger nuclease), and TALEN(transcription activator like effector nuclease) systems are threepotential methods through which CAR-T cells may be generated.

Definitions

The term “amino acid sequence” refers to a list of abbreviations,letters, characters or words representing amino acid residues. The aminoacid abbreviations used herein are conventional one letter codes for theamino acids and are expressed as follows: A, alanine; B, asparagine oraspartic acid; C, cysteine; D aspartic acid; E, glutamate, glutamicacid; F, phenylalanine; G, glycine; H histidine; I isoleucine; K,lysine; L, leucine; M, methionine; N, asparagine; P, proline; Q,glutamine; R, arginine; S, serine; T, threonine; V, valine; W,tryptophan; Y, tyrosine; Z, glutamine or glutamic acid.

The term “antibody” refers to an immunoglobulin, derivatives thereofwhich maintain specific binding ability, and proteins having a bindingdomain which is homologous or largely homologous to an immunoglobulinbinding domain. These proteins may be derived from natural sources, orpartly or wholly synthetically produced. An antibody may be monoclonalor polyclonal. The antibody may be a member of any immunoglobulin classfrom any species, including any of the human classes: IgG, IgM, IgA,IgD, and IgE. In exemplary embodiments, antibodies used with the methodsand compositions described herein are derivatives of the IgG class. Inaddition to intact immunoglobulin molecules, also included in the term“antibodies” are fragments or polymers of those immunoglobulinmolecules, and human or humanized versions of immunoglobulin moleculesthat selectively bind the target antigen.

The term “antibody fragment” refers to any derivative of an antibodywhich is less than full-length. In exemplary embodiments, the antibodyfragment retains at least a significant portion of the full-lengthantibody's specific binding ability. Examples of antibody fragmentsinclude, but are not limited to, Fab, Fab′, F(ab′)2, scFv, Fv, dsFvdiabody, Fc, and Fd fragments. The antibody fragment may be produced byany means. For instance, the antibody fragment may be enzymatically orchemically produced by fragmentation of an intact antibody, it may berecombinantly produced from a gene encoding the partial antibodysequence, or it may be wholly or partially synthetically produced. Theantibody fragment may optionally be a single chain antibody fragment.Alternatively, the fragment may comprise multiple chains which arelinked together, for instance, by disulfide linkages. The fragment mayalso optionally be a multimolecular complex. A functional antibodyfragment will typically comprise at least about 50 amino acids and moretypically will comprise at least about 200 amino acids.

The term “antigen binding site” refers to a region of an antibody thatspecifically binds an epitope on an antigen.

The term “aptamer” refers to oligonucleic acid or peptide molecules thatbind to a specific target molecule. These molecules are generallyselected from a random sequence pool. The selected aptamers are capableof adapting unique tertiary structures and recognizing target moleculeswith high affinity and specificity. A “nucleic acid aptamer” is a DNA orRNA oligonucleic acid that binds to a target molecule via itsconformation, and thereby inhibits or suppresses functions of suchmolecule. A nucleic acid aptamer may be constituted by DNA, RNA, or acombination thereof. A “peptide aptamer” is a combinatorial proteinmolecule with a variable peptide sequence inserted within a constantscaffold protein. Identification of peptide aptamers is typicallyperformed under stringent yeast dihybrid conditions, which enhances theprobability for the selected peptide aptamers to be stably expressed andcorrectly folded in an intracellular context.

The term “carrier” means a compound, composition, substance, orstructure that, when in combination with a compound or composition, aidsor facilitates preparation, storage, administration, delivery,effectiveness, selectivity, or any other feature of the compound orcomposition for its intended use or purpose. For example, a carrier canbe selected to minimize any degradation of the active ingredient and tominimize any adverse side effects in the subject.

The term “chimeric molecule” refers to a single molecule created byjoining two or more molecules that exist separately in their nativestate. The single, chimeric molecule has the desired functionality ofall of its constituent molecules. One type of chimeric molecules is afusion protein.

The term “engineered antibody” refers to a recombinant molecule thatcomprises at least an antibody fragment comprising an antigen bindingsite derived from the variable domain of the heavy chain and/or lightchain of an antibody and may optionally comprise the entire or part ofthe variable and/or constant domains of an antibody from any of the Igclasses (for example IgA, IgD, IgE, IgG, IgM and IgY).

The term “epitope” refers to the region of an antigen to which anantibody binds preferentially and specifically. A monoclonal antibodybinds preferentially to a single specific epitope of a molecule that canbe molecularly defined. In the present invention, multiple epitopes canbe recognized by a multispecific antibody.

The term “fusion protein” refers to a polypeptide formed by the joiningof two or more polypeptides through a peptide bond formed between theamino terminus of one polypeptide and the carboxyl terminus of anotherpolypeptide. The fusion protein can be formed by the chemical couplingof the constituent polypeptides or it can be expressed as a singlepolypeptide from nucleic acid sequence encoding the single contiguousfusion protein. A single chain fusion protein is a fusion protein havinga single contiguous polypeptide backbone. Fusion proteins can beprepared using conventional techniques in molecular biology to join thetwo genes in frame into a single nucleic acid, and then expressing thenucleic acid in an appropriate host cell under conditions in which thefusion protein is produced.

The term “Fab fragment” refers to a fragment of an antibody comprisingan antigen-binding site generated by cleavage of the antibody with theenzyme papain, which cuts at the hinge region N-terminally to theinter-H-chain disulfide bond and generates two Fab fragments from oneantibody molecule.

The term “F(ab′)2 fragment” refers to a fragment of an antibodycontaining two antigen-binding sites, generated by cleavage of theantibody molecule with the enzyme pepsin which cuts at the hinge regionC-terminally to the inter-H-chain disulfide bond.

The term “Fc fragment” refers to the fragment of an antibody comprisingthe constant domain of its heavy chain.

The term “Fv fragment” refers to the fragment of an antibody comprisingthe variable domains of its heavy chain and light chain.

“Gene construct” refers to a nucleic acid, such as a vector, plasmid,viral genome or the like which includes a “coding sequence” for apolypeptide or which is otherwise transcribable to a biologically activeRNA (e.g., antisense, decoy, ribozyme, etc), may be transfected intocells, e.g. in certain embodiments mammalian cells, and may causeexpression of the coding sequence in cells transfected with theconstruct. The gene construct may include one or more regulatoryelements operably linked to the coding sequence, as well as intronicsequences, polyadenylation sites, origins of replication, marker genes,etc.

The term “identity” refers to sequence identity between two nucleic acidmolecules or polypeptides. Identity can be determined by comparing aposition in each sequence which may be aligned for purposes ofcomparison. When a position in the compared sequence is occupied by thesame base, then the molecules are identical at that position. A degreeof similarity or identity between nucleic acid or amino acid sequencesis a function of the number of identical or matching nucleotides atpositions shared by the nucleic acid sequences. Various alignmentalgorithms and/or programs may be used to calculate the identity betweentwo sequences, including FASTA, or BLAST which are available as a partof the GCG sequence analysis package (University of Wisconsin, Madison,Wis.), and can be used with, e.g., default setting. For example,polypeptides having at least 70%, 85%, 90%, 95%, 98% or 99% identity tospecific polypeptides described herein and preferably exhibitingsubstantially the same functions, as well as polynucleotide encodingsuch polypeptides, are contemplated. Unless otherwise indicated asimilarity score will be based on use of BLOSUM62. When BLASTP is used,the percent similarity is based on the BLASTP positives score and thepercent sequence identity is based on the BLASTP identities score.BLASTP “Identities” shows the number and fraction of total residues inthe high scoring sequence pairs which are identical; and BLASTP“Positives” shows the number and fraction of residues for which thealignment scores have positive values and which are similar to eachother. Amino acid sequences having these degrees of identity orsimilarity or any intermediate degree of identity of similarity to theamino acid sequences disclosed herein are contemplated and encompassedby this disclosure. The polynucleotide sequences of similar polypeptidesare deduced using the genetic code and may be obtained by conventionalmeans, in particular by reverse translating its amino acid sequenceusing the genetic code.

The term “linker” is art-recognized and refers to a molecule or group ofmolecules connecting two compounds, such as two polypeptides. The linkermay be comprised of a single linking molecule or may comprise a linkingmolecule and a spacer molecule, intended to separate the linkingmolecule and a compound by a specific distance.

The term “multivalent antibody” refers to an antibody or engineeredantibody comprising more than one antigen recognition site. For example,a “bivalent” antibody has two antigen recognition sites, whereas a“tetravalent” antibody has four antigen recognition sites. The terms“monospecific”, “bispecific”, “trispecific”, “tetraspecific”, etc. referto the number of different antigen recognition site specificities (asopposed to the number of antigen recognition sites) present in amultivalent antibody. For example, a “monospecific” antibody's antigenrecognition sites all bind the same epitope. A “bispecific” antibody hasat least one antigen recognition site that binds a first epitope and atleast one antigen recognition site that binds a second epitope that isdifferent from the first epitope. A “multivalent monospecific” antibodyhas multiple antigen recognition sites that all bind the same epitope. A“multivalent bispecific” antibody has multiple antigen recognitionsites, some number of which bind a first epitope and some number ofwhich bind a second epitope that is different from the first epitope.

The term “nucleic acid” refers to a natural or synthetic moleculecomprising a single nucleotide or two or more nucleotides linked by aphosphate group at the 3′ position of one nucleotide to the 5′ end ofanother nucleotide. The nucleic acid is not limited by length, and thusthe nucleic acid can include deoxyribonucleic acid (DNA) or ribonucleicacid (RNA).

The term “operably linked to” refers to the functional relationship of anucleic acid with another nucleic acid sequence. Promoters, enhancers,transcriptional and translational stop sites, and other signal sequencesare examples of nucleic acid sequences operably linked to othersequences. For example, operable linkage of DNA to a transcriptionalcontrol element refers to the physical and functional relationshipbetween the DNA and promoter such that the transcription of such DNA isinitiated from the promoter by an RNA polymerase that specificallyrecognizes, binds to and transcribes the DNA.

The terms “peptide,” “protein,” and “polypeptide” are usedinterchangeably to refer to a natural or synthetic molecule comprisingtwo or more amino acids linked by the carboxyl group of one amino acidto the alpha amino group of another.

The term “pharmaceutically acceptable” refers to those compounds,materials, compositions, and/or dosage forms which are, within the scopeof sound medical judgment, suitable for use in contact with the tissuesof human beings and animals without excessive toxicity, irritation,allergic response, or other problems or complications commensurate witha reasonable benefit/risk ratio.

The terms “polypeptide fragment” or “fragment”, when used in referenceto a particular polypeptide, refers to a polypeptide in which amino acidresidues are deleted as compared to the reference polypeptide itself,but where the remaining amino acid sequence is usually identical to thatof the reference polypeptide. Such deletions may occur at theamino-terminus or carboxy-terminus of the reference polypeptide, oralternatively both. Fragments typically are at least about 5, 6, 8 or 10amino acids long, at least about 14 amino acids long, at least about 20,30, 40 or 50 amino acids long, at least about 75 amino acids long, or atleast about 100, 150, 200, 300, 500 or more amino acids long. A fragmentcan retain one or more of the biological activities of the referencepolypeptide. In various embodiments, a fragment may comprise anenzymatic activity and/or an interaction site of the referencepolypeptide. In another embodiment, a fragment may have immunogenicproperties.

The term “protein domain” refers to a portion of a protein, portions ofa protein, or an entire protein showing structural integrity; thisdetermination may be based on amino acid composition of a portion of aprotein, portions of a protein, or the entire protein.

The term “single chain variable fragment or scFv” refers to an Fvfragment in which the heavy chain domain and the light chain domain arelinked. One or more scFv fragments may be linked to other antibodyfragments (such as the constant domain of a heavy chain or a lightchain) to form antibody constructs having one or more antigenrecognition sites.

A “spacer” as used herein refers to a peptide that joins the proteinscomprising a fusion protein. Generally a spacer has no specificbiological activity other than to join the proteins or to preserve someminimum distance or other spatial relationship between them. However,the constituent amino acids of a spacer may be selected to influencesome property of the molecule such as the folding, net charge, orhydrophobicity of the molecule.

The term “specifically binds”, as used herein, when referring to apolypeptide (including antibodies) or receptor, refers to a bindingreaction which is determinative of the presence of the protein orpolypeptide or receptor in a heterogeneous population of proteins andother biologics. Thus, under designated conditions (e.g. immunoassayconditions in the case of an antibody), a specified ligand or antibody“specifically binds” to its particular “target” (e.g. an antibodyspecifically binds to an endothelial antigen) when it does not bind in asignificant amount to other proteins present in the sample or to otherproteins to which the ligand or antibody may come in contact in anorganism. Generally, a first molecule that “specifically binds” a secondmolecule has an affinity constant (Ka) greater than about 10⁵ M⁻¹ (e.g.,10⁶ M⁻¹, 10⁷ M⁻¹, 10⁸ M⁻¹, 10⁹ M⁻¹, 10¹⁰ M⁻¹, 10¹¹ M⁻¹, and 10¹² M⁻¹ ormore) with that second molecule.

The term “specifically deliver” as used herein refers to thepreferential association of a molecule with a cell or tissue bearing aparticular target molecule or marker and not to cells or tissues lackingthat target molecule. It is, of course, recognized that a certain degreeof non-specific interaction may occur between a molecule and anon-target cell or tissue. Nevertheless, specific delivery, may bedistinguished as mediated through specific recognition of the targetmolecule. Typically specific delivery results in a much strongerassociation between the delivered molecule and cells bearing the targetmolecule than between the delivered molecule and cells lacking thetarget molecule.

The term “subject” refers to any individual who is the target ofadministration or treatment. The subject can be a vertebrate, forexample, a mammal. Thus, the subject can be a human or veterinarypatient. The term “patient” refers to a subject under the treatment of aclinician, e.g., physician.

The term “therapeutically effective” refers to the amount of thecomposition used is of sufficient quantity to ameliorate one or morecauses or symptoms of a disease or disorder. Such amelioration onlyrequires a reduction or alteration, not necessarily elimination.

The terms “transformation” and “transfection” mean the introduction of anucleic acid, e.g., an expression vector, into a recipient cellincluding introduction of a nucleic acid to the chromosomal DNA of saidcell.

The term “treatment” refers to the medical management of a patient withthe intent to cure, ameliorate, stabilize, or prevent a disease,pathological condition, or disorder. This term includes activetreatment, that is, treatment directed specifically toward theimprovement of a disease, pathological condition, or disorder, and alsoincludes causal treatment, that is, treatment directed toward removal ofthe cause of the associated disease, pathological condition, ordisorder. In addition, this term includes palliative treatment, that is,treatment designed for the relief of symptoms rather than the curing ofthe disease, pathological condition, or disorder; preventativetreatment, that is, treatment directed to minimizing or partially orcompletely inhibiting the development of the associated disease,pathological condition, or disorder; and supportive treatment, that is,treatment employed to supplement another specific therapy directedtoward the improvement of the associated disease, pathologicalcondition, or disorder.

The term “variant” refers to an amino acid or peptide sequence havingconservative amino acid substitutions, non-conservative amino acidsubsitutions (i.e. a degenerate variant), substitutions within thewobble position of each codon (i.e. DNA and RNA) encoding an amino acid,amino acids added to the C-terminus of a peptide, or a peptide having60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% sequence identity to areference sequence.

The term “vector” refers to a nucleic acid sequence capable oftransporting into a cell another nucleic acid to which the vectorsequence has been linked. The term “expression vector” includes anyvector, (e.g., a plasmid, cosmid or phage chromosome) containing a geneconstruct in a form suitable for expression by a cell (e.g., linked to atranscriptional control element).

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, other embodiments are within the scope of the followingclaims.

EXAMPLES Example 1: Screen for Anti-AML Antibodies

EL4 mouse lymphoma cells that express immunogen or irrelevant antigenwere screened for anti-AML antibody binding. As shown in FIG. 1,EL4-empty, EL4-CD123, and EL4-CD33 cells were incubated together in eachwell of a 96 well plate. In addition an anti-CD123 PE antibody andhybridoma antibody, with putative anti-C33 reactivity, was included inthe culture. The antibodies and cells were co-incubated, washed, andstained with Rat anti-mouse IgG APC. Positive binding was revealed byflow cytometry as anti-CD33/APC⁺ and anti-CD123/PE⁻.

As illustrated in FIG. 2, chosen antibodies were subjected to asecondary, functional screening with Jurkat cells that express a CARdocking platform for antibodies and target cells. These antibodies werescreened for T cell activation. 24 clones were selected based on EL4binding. EL4 CD33 (target) and EL4-CD123 (negative control) wereincubated with Jurkat mCD16 or mCD32 with its NFκB/RE GFP reporter. SeeTable 7.

TABLE 7 EL4  6A11 13G6 16H8 17G8 18D8 25B1 26C8 27A3 27B5 27B12 27E1228H1 CD123/ 29A11 29C3 29F4 31E7 32D11 35F11 33G3 35D5 36C2 37D9 38A1038G5 Jurkat mCD16- GFP EL4  6A11 13G6 16H8 17G8 18D8 25B1 26C8 27A3 27B527B12 27E12 28H1 CD33/ 29A11 29C3 29F4 31E7 32D11 35F11 33G3 35D5 36C237D9 38A10 38G5 Jurkat mCD16- GFP EL4  6A11 13G6 16H8 17G8 18D8 25B126C8 27A3 27B5 27B12 27E12 28H1 CD123/ 29A11 29C3 29F4 31E7 32D11 35F1133G3 35D5 36C2 37D9 38A10 38G5 Jurkat mCD32- GFP EL4  6A11 13G6 16H817G8 18D8 25B1 26C8 27A3 27B5 27B12 27E12 28H1 CD33/ 29A11 29C3 29F431E7 32D11 35F11 33G3 35D5 36C2 37D9 38A10 38G5 Jurkat mCD32- GFP

1×10⁴ EL4-CD123 or EL4-CD33 cells were cultured into wells of a 96 wellplate. Hybridoma supernatant, which included the putative anti-AMLantibodies, were added to the culture media. Jurkat cells were modifiedto include either a CD16 or CD32 Fc receptor conjugated to human 41BBand CD3zeta. In addition, these Jurkat cells have a transgene GFP thatis controlled by NFKB-responsive elements. The EL4 targets, hybridomaantibodies, and 1×10⁴ Jurkat cells were incubated overnight and antibodyligation and Jurkat T cell activation was measured by GFP flow cytometry(FIG. 3).

The same 24 clones were screened (Table 8) using EL4 CD33 (target) andCD123 (negative control), and anti-IgG/APC antibody to re-verify bindingby flow cytometry. See Table 9 for results.

TABLE 8 EL4  6A11 13G6 16H8 17G8 18D8 25B1 26C8 27A3 27B5 27B12 27E1228H1 CD33/ 29A11 29C3 29F4 31E7 32D11 35F11 33G3 35D5 36C2 37D9 38A1038G5 IgG APC EL4  6A11 13G6 16H8 17G8 18D8 25B1 26C8 27A3 27B5 27B1227E12 28H1 CD123/ 29A11 29C3 29F4 31E7 32D11 35F11 33G3 35D5 36C2 37D938A10 38G5 IgG APC

TABLE 9 Clone CD33/APC+ CD123/APC+ Difference 6A11 1.92 21.18 −19.2618D8 50.07 20.97 29.1 27A3 54.76 27.05 27.71 33G3 62.85 21.50 41.35 35D563.34 18.84 44.5 36C2 70.49 15.01 55.48 37D9 67.37 13.11 54.26 38G555.63 19.95 35.68

Six CD33 Clones were selected after EL4 binding and Jurkat activationscreening (Table 10).

TABLE 10 Hybridoma Binding Activation Clone (APC+ %) (GFP+ %) 27A3 55 3733G3 63 35 36C2 70 34 6A11 2 20 35D5 63 7 38G5 56 6

FIGS. 4A to 4D are CD33 CAR diagrams for 6A11HC1_LC (FIG. 4A),6A11HC2_LC (FIG. 4B), 27A3HC_LC1 (FIG. 4C), 27A3HC_LC2 (FIG. 4D), and27A3HC_LC3 (FIG. 4E).

Example 2: CD33-Targeted CAR-T Cells

CD33-targeted CAR T cells were generated as described. Briefly, T cellswere isolated by density gradient centrifugation followed by a T-Cellisolation kit (Stem Cells) and stimulated with anti-CD3 and anti-CD28beads in RPMI with recombinant human IL-2. Activated T cells weretransduced on RetroNectin coated plates with anti-CD33 CAR retrovirusprepared form H29 and RD114 packaging cells. CD33 CAR T cells werede-beaded after approximately 7 days and evaluated for gene transferprior to use in experiments. Mock transduced T cells (UN) were used as acontrol.

FIG. 5 is a bar graph showing CD33 gene transfer on T cell subsets. Genetransfer was assessed as % CD3+ and mcherry+ on live T cells. Afterde-beading T cells were stained with CD3, CD8 and CD4 (monoclonalantibodies and analyzed by using a flow cytometer.

FIG. 6 is a graph showing results of a CD33 CART cell cytotoxicityassay. Activated CD33 CAR T cells or mock transduced T cells wereco-cultured with target CHO CD33 cells, and cytotoxicity was measured ona real time cell analysis system. The data are presented as the averagenormalized cell index over time for duplicate wells. CD33 CHO cells wereleft to adhere for 16 hours to xCELLigence E-plates. CD33 CAR T cells oractivated mock transduced T cells were added to the wells of E-plateswith target cells at an E:T ratio of 10:1 for 6 days. Normalized cellindex is calculated as cell index at a given time point divided by cellindex at the normalized time point which is day 1 after addition of Tcells.

FIG. 7 is a graph showing CD33 CART cell proliferation. Activated CD33CAR T cells or un-transduced T cells were co-cultured with target CHOCD33 cells. CART cells were counted on indicated days.

FIGS. 8A to 8C are bar graph showing CD33 CART cell cytokine production.CD33 CAR T cells or mock transduced T cells were co-cultured with targetCHO CD33 cells for 24 hours. Supernatants were collected and thecytokines IFN-γ (FIG. 8A), TNF-α (FIG. 8B), and IL-6 (FIG. 8C) wereanalyzed via Luminex.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of skill in the artto which the disclosed invention belongs. Publications cited herein andthe materials for which they are cited are specifically incorporated byreference.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

1. A chimeric antigen receptor (CAR) polypeptide, comprising a CD33antigen binding domain, a transmembrane domain, an intracellularsignaling domain, and a co-stimulatory signaling region.
 2. Thepolypeptide of claim 1, wherein the CD33 antigen binding domain is asingle-chain variable fragment (scFv) of an antibody that specificallybinds CD33.
 3. The polypeptide of claim 2, wherein the anti-CD33 scFvV_(H) domain comprises the amino acid sequence SEQ ID NO:22, SEQ IDNO:23, or SEQ ID NO:24.
 4. The polypeptide of claim 2, wherein theanti-CD33 scFv V_(L) domain comprises the amino acid sequence SEQ IDNO:25, SEQ ID NO:26, SEQ ID NO:27, or SEQ ID NO:28.
 5. The polypeptideof claim 1, wherein the costimulatory signaling region comprises thecytoplasmic domain of a costimulatory molecule selected from the groupconsisting of CD27, CD28, 4-1BB, OX40, CD30, CD40, PD-1, ICOS,lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT,NKG2C, B7-H3, a ligand that specifically binds with CD83, and anycombination thereof
 6. The polypeptide of claim 1, wherein the CARpolypeptide is defined by the formula:SP-CD33-HG-TM-CSR-ISD; orSP-CD33-HG-TM-ISD-CSR wherein “SP” represents a signal peptide, wherein“CD33” represents a CD33-binding region, wherein “HG” represents andoptional hinge domain, wherein “TM” represents a transmembrane domain,wherein “CSR” represents a co-stimulatory signaling region, wherein“ISD” represents an intracellular signaling domain, and wherein “-”represents a bivalent linker.
 7. The polypeptide of claim 1, wherein theintracellular signaling domain comprises a CD3 zeta (CD3ζ) signalingdomain.
 8. An isolated nucleic acid sequence encoding the recombinantpolypeptide of claim
 1. 9. A vector comprising the isolated nucleic acidsequence of claim
 8. 10. A cell comprising the vector of claim
 9. 11.The cell of claim 10, wherein the cell is selected from the groupconsisting of an αβT cell, γδT cell, a Natural Killer (NK) cells, aNatural Killer T (NKT) cell, a B cell, an innate lymphoid cell (ILC), acytokine induced killer (CIK) cell, a cytotoxic T lymphocyte (CTL), alymphokine activated killer (LAK) cell, a regulatory T cell, or anycombination thereof.
 12. The cell of claim 11, wherein the cell exhibitsan anti-tumor immunity when the antigen binding domain of the CAR bindsto CD33.
 13. The cell of claim 11, wherein the cell further comprise asecond CAR polypeptide comprising a CD33 antigen binding domain, whereinthe cell exhibits an anti-tumor immunity when both the antigen bindingdomain of the CAR binds to CD33 and the antigen binding domain of thesecond CAR binds to CD123.
 14. A method of providing an anti-cancerimmunity in a subject with a CD33-expressing cancer, the methodcomprising administering to the subject an effective amount of an immuneeffector cell genetically modified to express the CAR polypeptide ofclaim 1, thereby providing an anti-tumor immunity in the mammal.
 15. Themethod of claim 14, wherein the immune effector cell is selected fromthe group consisting of a T cell, a Natural Killer (NK) cell, acytotoxic T lymphocyte (CTL), and a regulatory T cell.
 16. The method ofclaim 14, further comprising administering to the subject a checkpointinhibitor.
 17. The method of claim 16, wherein the checkpoint inhibitorcomprises an anti-PD-1 antibody, anti-PD-L1 antibody, anti-CTLA-4antibody, or a combination thereof.
 18. The method of claim 14, whereinthe cancer comprises myelodysplastic syndromes, acute myeloid leukemia,or bi-phenotypic leukemia.
 19. A fusion polypeptide comprising thefollowing formula:V_(L)I-V_(H)I-V_(L)T-V_(H)T,V_(L)T-V_(H)T-V_(L)I-V_(H)I,V_(H)T-V_(L)T-V_(H)I-V_(L)I,V_(H)I-V_(L)I-V_(H)T-V_(L)T,V_(L)I-V_(H)I-V_(H)T-V_(L)T,V_(L)T-V_(H)T-V_(H)I-V_(L)I, wherein “V_(L)I” is a light chain variabledomain specific for an immune cell antigen; wherein “V_(H)T” is a heavychain variable domain specific for CD33; wherein “V_(L)T” is a lightchain variable domain specific for CD33; wherein “V_(H)I” is a heavychain variable domain specific for the immune cell antigen; wherein “-”consists of a peptide linker or a peptide bond.
 20. A method fortreating cancer in a subject, comprising administering to the subject atherapeutically effective amount of the fusion polypeptide of claim 19in a pharmaceutically acceptable carrier.